Nitric oxide donor compounds

ABSTRACT

The invention relates to nitric oxide donor compounds and their use for treating cardiovascular diseases, inflammation, pain, fever, gastrointestinal disorders, ophthalmic diseases, hepatic disorders, renal diseases, respiratory disorders, immunological diseases, bone metobolismsdysfunctions, central and peripheral nervous system diseases, sexual dysfunctions, infectious diseases, for the inhibition of platelet aggregation and platelet adhesion, for treating pathological conditions resulting from abnormal cell proliferation, vascular diseases. The invention also relates to compositions comprising at least one nitric oxide releasing compounds of the invention and composition comprising at least one nitric oxide releasing compounds according to the invention and at least one 15 therapeutic agent.

The invention relates to nitric oxide donor compounds and theirpharmaceutical compositions. The invention also relates to novelcompositions comprising at least one nitric oxide releasing compoundsand at least one therapeutic agent.

The invention also relates to the use of the nitric oxide donorcompounds and their compositions for treating cardiovascular diseases,inflammation, pain, fever, gastrointestinal disorders, ophthalmicdiseases, hepatic disorders, renal diseases, respiratory disorders,immunological diseases, bone metabolism dysfunctions, central andperipheral nervous system diseases, sexual dysfunctions, infectiousdiseases, for the inhibition of platelet aggregation and plateletadhesion, for treating pathological conditions resulting from abnormalcell proliferation, vascular diseases.

Nitric oxide (commonly referred to as NO) has been implicated in a widerange of biological functions. As a result, NO, and materials thatrelease NO, are candidate therapeutics for a range of diverse diseasestates.

Nitric oxide donor compounds have been used for many years in thetreatment of various clinical conditions, particularly coronary arterydisease. The nitrovasodilators such as Nitroglycerin (GTN) has been usedfor the treatment of various types of myocardial ischemia. Because ofits pathogenic nature (chronicity with acute exacerbation), prophylacticand acute treatments are necessary to prevent complications withpotentially fatal outcomes (>25% death for acute MI). Particularly thephenomenon of tolerance to the anti-anginal effects of GTN and to allother existing organic nitrates is of a special clinical significance.Early development of tolerance to the drug is by far the most seriousdrawback of nitrate therapy.

Other known methods of NO delivery include soluble, short-term NOdonors, such as S-nitroso-N-acetyl-D,L-penicillamine (SNAP) andincorporation of NO donors into polymeric matrices. In general,NO-nucleophile complexes (e.g., diazeniumdiolate ions) and NO-donatinggroups (e.g., S-nitrosothiols) may spontaneously decompose in aqueousenvironments, such as physiological or bodily fluids, to release NO.This rapid, spontaneous decomposition, however, may not be a favourableproperty for many therapeutic applications. Generally, a slower rate ofdecomposition and more steady evolution of NO are more efficacious.

Many of the existing NO donors must be administered intravenously, whichresults in rapid onset of decreasing blood pressure accompanied byunwanted side effects. Their effect does not extend beyond the period ofinfusion. Another undesirable side effect of some NO donors includes anincrease in heart rate. A need exists for an NO donor compound to treatdiseases that does not induce undesirable side effects.

The invention is directed to compounds that are particularly useful asnitric oxide donors having an improved pharmacological profile.

The invention provides compounds of the formula (I) and pharmaceuticallyacceptable salts or stereoisomers thereof

wherein:s is 1;s′ and s″ are independently selected from 0 or 1, preferably s′ or s″ is1 or s′ and s″ are both 0;m, m′ and m″ are each independently selected from 0 or 1 with theproviso that when m, m′ or m″ are 0, A is linked directly to the groups—(Y—ONO₂), —(Y′—ONO₂), —(Y″—ONO₂), preferably at least one of m, m′ orm″ is 1, or more preferably m, m′ and m″ are 0,B at each occurrence is independently selected from:

preferably B is

A is a radical selected from the group consisting of:

wherein:in formulas (IIa)-(IIm) and (IIo)-(IIu), R₁ is selected from: H,—C(O)O—C(CH₃)₃, —C(O)O—R_(1x), —C(O)O—R_(1x), wherein R_(1x) is one ofthe groups —[(B)_(m)—(Y—ONO₂)]_(s), —[(B)_(m′)—(Y′—ONO₂]_(s′), or—[(B)_(m″)—(Y″—ONO₂)]_(s″) of formula (I) wherein m, m′ and m″ are 0 andY, Y′ and Y″ are as below reported;in formulas (IIa)-(IIu) R₂ is selected from:—C(O)OH, —C(O)—OC(CH₃)₃, —C(O)OR_(2x), —C(O)NHR_(2xx),—C(O)N(CH₃)R_(2xx) wherein R_(2x) is one of the groups—[(B)_(m)—(Y—ONO₂)]_(s), —[(B)_(m′)—(Y′—ONO₂)]_(s′) or—[(B)_(m″)—(Y″—ONO₂)]_(s″) of formula (I) wherein m, m′ and m″ are 0 or1, B is as above defined and Y, Y′ and Y″ are as below reported,R_(2xx) is one of the groups —[(B)_(m)—(Y—ONO₂)]_(s),—[(B)_(m′)—(Y′—ONO₂)]_(s′) or —[(B)_(m″)—(Y″—ONO₂)]_(s″) of formula (I)wherein m, m′ and m″ are 0 and Y, Y′ and Y″ are as below reported,or R₂ is the group R₄:

in formula (IIa), R_(a) is selected from the groups consisting of:a) —H, —CH₃, isopropyl, isobutyl, sec-butyl, tert-butyl,methylthio-(CH₂)₂—, phenyl, benzyl, C₆H₅—CH₂—CH₂—, 2-monosubstitutedbenzyl, or 3-monosubstituted benzyl or 4-monosubstituted benzyl withgroups such as —F, —Cl, I, —NO₂, —CF₃, —CH₃, CN, C₆H₅CO—;or R_(a) is 2,4-dichlorobenzyl, 3,4-dichlorobenzyl, 3,4-difluorobenzyl,3-triptophanyl-CH₂—, 3-benzothienyl-CH₂—, 4-imidazolyl-CH₂—,9-anthranyl-CH₂—, cyclohexyl, cyclohexyl-CH₂—, cyclohexyl—(CH₂)₂—,cyclopentyl-CH₂—, (C₆H₅)₂CH—, 4-quinolyl-CH₂—, 3-quinolyl-CH₂—,2-quinolyl-CH₂—, 2-quinoxalyl-CH₂—, 2-furyl-CH₂—, 1-naphtyl-CH₂—,2-naphtyl-CH₂—, 2-pyridyl-CH₂—, 3-Pyridyl-CH₂—, 4-pyridyl-CH₂—,2-thienyl-CH₂—, 3-thienyl-CH₂—, C₆H₄—CH═CH—CH₂—, CH₂═CH—CH₂—,CH≡CH—CH₂—, NH₂—CO—CH₂—, NH₂—OC—(CH₂)₂—, or —P(═O) (OCH₃)₂;b) HS—CH₂—, R_(bx)—C(O)—S—CH₂—, R_(bx)—OC(O)—S—CH₂—,R_(bx)—NH—C(O)S—CH₂— wherein R_(bx) is one of the groups—[(B)_(m)—(Y—ONO₂)]_(s), —[(B)_(m′)—(Y′—ONO₂)]_(s′), or—[(B)_(m″)—(Y″—ONO₂)]_(s″) of formula (I) wherein m, m′ and m″ are 0 andY, Y′ and Y″ are as below defined;c) R_(x)O—CH₂—, R_(x)O—CH(CH₃)—, (R_(x)O)-p-C₆H₄—CH₂—,4-(R_(x)O)-3,5-diiodobenzyl-, 4-(R_(x)O)-3-nitrobenzyl- wherein R_(x) isH, R_(xx)—C(O)—, R_(xx)—OC(O)—, R_(xx)—NHC(O)— wherein R_(xx) is one ofthe groups —[(B)_(m)—(Y—ONO₂)]_(s), —[(B)_(m′)—(Y′—ONO₂)]_(s′) or—[(B)_(m″)—(Y″—ONO₂)]_(s″) of formula (I) wherein m, m′ and m″ are 0 andY, Y′ and Y″ are as below defined;d) R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂—, R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—,wherein R_(g) is OH, (CH₃)₃CO—, R_(gx)—O—, R_(gxx)—NH—, R_(gxx)—N(CH₃)—wherein R_(gx) is one of the groups —[(B)_(m)—(Y—ONO₂)]_(s),—[(B)_(m′)—(Y′—ONO₂)]_(s′) or —[(B)_(m″)—Y″—ONO₂)]_(s″) of formula (I)wherein m, m′ and m″ are 0 or 1, B is as above defined and Y, Y′ and Y″are as below reported, R_(gxx) is one of the groups—[(B)_(m)—(Y—ONO₂)]_(s), —[(B)_(m′)—(Y′—ONO₂)]_(s′) or—[(B)_(m″)—(Y″—ONO₂)]_(s″) of formula (I) wherein m, m′ and m″ are 0 andY, Y′ and Y″ are as below reported,or R_(g) is the group R_(gg):

e) R_(h)NH(CH₂)_(p)— or R_(i)NH(═NH)NH—(CH₂)₃—, wherein p is an integerfrom 0 to 4, R_(h) is H, (CH₃)₃C—OC(O)—, R_(hh)—C(O)— or R_(hh)—OC(O)—,R_(i) is H, R_(ii)—C(O)— or R_(ii)—C(O)—, wherein R_(hh) and R_(ii) areeach independently one of the groups —[(B)_(m)—(Y—ONO₂)]_(s),—[(B)_(m′)—(Y′—ONO₂)]_(s′) or [(B)_(m″)—(Y″—ONO₂)]_(s″) of formula (I)wherein m, m′ and m″ are 0 and Y, Y′ and Y″ are as below defined;in formula (IIc) R_(c) is selected from the following groups:a′) H, CH₃, isopropyl, isobutyl, sec-butyl, methylthio-(CH₂)₂—, phenyl,benzyl, biphenyl-CH₂, 3-triptophanyl-CH₂—, NH₂—CO—CH₂—, NH₂—CO—(CH₂)₂—;b′) HS—CH₂—, R_(bx)—C(O)—S—CH₂—, R_(bx)—OC(O)—S—CH₂—,R_(bx)—NH—C(O)S—CH₂— wherein R_(bx) is one of the groups—[(B)_(m)—(Y—ONO₂)]_(s), —[(B)_(m′)—(Y′—ONO₂)]_(s′) or—[(B)_(m″)—(Y″—ONO₂)]_(s″) of formula (I) wherein m, m′ and m″ are 0 andY, Y′ and Y″ are as below defined;c′) R_(x)O—CH₂—, R_(x)O—CH(CH₃)—, R_(x)O—C₆H₄—CH₂— wherein R_(x) is H,R_(xx)—C(O)—, R_(xx)—OC(O)—, R_(xx)—NHC(O)— wherein R_(xx) is one of thegroups —[(B)_(m)—(Y—ONO₂)]_(s′), [(B′)_(m′)—(Y′—ONO₂)]_(s′) or—[(B″)_(m″)—(Y″—ONO₂)]_(s″) of formula (I) wherein m, m′ and m″ are 0and Y, Y′ and Y″ are as below defined;d′) R_(g)C(O)CH₂—, R_(g)C(O)(CH₂)₂— wherein R_(g) is OH, (CH₃)₃CO—,R_(gx)—O—, R_(gxx)—NH—, R_(gxx)—N(CH₃)— wherein R_(gx) is one of thegroups —[(B)_(m)—(Y—ONO₂)]_(s), —[(B)_(m′)—(Y′—ONO₂)]_(s′) or—[(B)_(m″)—(Y″—ONO₂)]_(s″) of formula (I) wherein m, m′ and m″ are 0 or1, B is as above defined and Y, Y′ and Y″ are as below reported,R_(gxx) is one of the groups —[(B)_(m)—(Y—ONO₂)]_(s),—[(B)_(m′)—(Y′—ONO₂)]_(s′) or —[(B)_(m″)—(Y″—ONO₂)]_(s″) of formula (I)wherein m, m′ and m″ are 0 and Y, Y′ and Y″ are as below reported;e′) R_(h)NH(CH₂)_(p)— or R_(i)NH(═NH)NH—(CH₂)₃—, wherein p is an integerfrom 0 to 4, R_(h) is H, (CH₃)₃C—OC(O)—, R_(hh)—C(O)— or R_(hh)—OC(O)—,R_(i) is H, R_(ii)—C(O)— or R_(ii)—OC(O)—, wherein R_(hh) and R_(ii) areeach independently one of the groups —[(B)_(m)—(Y—ONO₂)]_(s),—[(B)_(m′)—(Y′—ONO₂)]_(s′) or —[(B)_(m″)—(Y″—ONO₂)]_(s″) of formula (I)wherein m, m′ and m″ are 0 and Y, Y′ and Y″ are as below defined;in formula (IIf) Ph is phenyl, a′ is equal to 0, 1, 2, or 3, and a isequal to 0 or 1 with the proviso that a is 0 or 1 when a′ is 0 and a is0 when a′ is 1, 2 or 3;in formula (IIi) the group R₂ can be attached to one of the positions 1,2 or 3 of the cyclohexyl ring;in formulae (IIj) and (IIk) the symbol

represents a single bond or a double bond;in formula (Ilk) the group R₂ can be attached to one of the positions 1,2 or 3 of the piperidyl ring;in formula (IIl), R_(L) is selected from:H, methyl, propyl, allyl, (C₆H₅)₂CH—, 1-naphtyl-CH₂—, benzyl,2-bromobenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-fluorobenzyl,4-bromobenzyl, 4-methylbenzyl;in formula (IIm) R_(m) is selected from:benzyl, 2-bromobenzyl, 4-bromobenzyl, 4-methylbenzyl;in formula (IIn) R_(n) is selected from:—H, —C(O)—R_(nx), —C(O)O—R_(nx) or —(CH₂)₂—NH—R_(h) wherein R_(h) is —H,—C(O)O—C(CH₃)₃, —C(O)—R_(hh), —C(O)O—R_(hh) wherein R_(nx) and R_(hh)are each independently one of the groups —[(B)_(m)—(Y—ONO₂)]_(s),—[(B)_(m′)—(Y′—ONO₂)]_(s′) or —[(B)_(m″)—(Y″—ONO₂)]_(s″) of formula (I)wherein m, m′ and m″ are 0 and Y, Y′ and Y″ are as below defined;in formula (IIp), c is 0 or 1 and R₂ can be attached to the position 1,2 or 3 of the phenyl ring;in formula (IIs), R₃ is selected from:OH, —OC(O)—R_(3x), —OC(O)O—R_(3x), —OC(O)—NH—R_(3x) wherein R_(3x) isone of the groups —[(B)_(m)—(Y—ONO₂)]_(s), —[(B)_(m)′—(Y′—ONO₂)]_(s′) or—[(B)_(m″)—(Y″—ONO₂)]_(s″) of formula (I) wherein m, m′ and m″ are 0 andY, Y′ and Y″ are as below defined;in formula (IIs) R_(s) is selected from the following groups:a″) —H, —CH₃, isopropyl, isobutyl, sec-butyl, tert-butyl,methylthio—(CH₂)₂—, benzyl, 2-monosubstituted benzyl, or3-monosubstituted benzyl, 3-triptophanyl-CH₂—, 4-imidazolyl-CH₂—,NH₂—CO—CH₂—, NH₂—CO—(CH₂)₂—;b″) HS—CH₂—, R_(bx)—C(O)—S—CH₂—, R_(bx)—OC(O)—S—CH₂—,R_(bx)—NH—C(O)S—CH₂— wherein R_(bx) is one of the groups—[(B)_(m)—(Y—ONO₂)]_(s), —[(B)_(m′)—(Y′—ONO₂)]_(s′) or—[(B)_(m″)—(Y″—ONO₂)]_(s″) of formula (I) wherein m, m′ and m″ are 0 andY, Y′ and Y″ are as below defined;c″) R_(x)O—CH₂—, R_(x)O—CH(CH₃)—, (R_(x)O)-p-C₆H₄—CH₂—,4-(R_(x)O)-3,5-diiodobenzyl-, 4-(R_(x)O)-3-nitrobenzyl- wherein R_(x) isH, R_(xx)—C(O)—, R_(xx)—OC(O)—, R_(xx)—NHC(O)— wherein R_(xx) is one ofthe groups —[(B)_(m)—(Y—ONO₂)]_(s), —[(B)_(m′)—(Y′—ONO₂)]_(s′) or—[(B)_(m″)—(Y″—ONO₂)]_(s″) of formula (I) wherein m, m′ and m″ are 0 andY, Y′ and Y″ are as below defined;d″) R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—,wherein R_(g) is OH, (CH₃)₃CO—, R_(gx)—O—, R_(g)—NH—, R_(gxx)—N(CH₃)—wherein R_(gx) is one of the groups —[(B)_(m)—(Y—ONO₂)]_(s),—[(B)_(m′)—(Y′—ONO₂)]_(s′) or —[(B)_(m″)—(Y″—ONO₂)]_(s″) of formula (I)wherein m, m′ and m″ are 0 or 1, B is as above defined and Y, Y′ and Y″are as below reported, R_(gxx) is one of the groups—[(B)_(m)—(Y—ONO₂)]_(s), —[(B)_(m′)—(Y′—ONO₂)]_(s′) or—[(B)_(m″)—(Y″—ONO₂)]_(s″) of formula (I) wherein m, m′ and m″ are 0 andY, Y′ and Y″ are as below reported,e″) R_(h)NH(CH₂)_(p)— or R_(i)NH(═NH)NH—(CH₂)₃—, wherein p is an integerfrom 0 to 4, R_(h) is H, (CH₃)₃C—OC(O)—, R_(hh)—C(O)— or R_(hh)—OC(O)—,R_(i) is H, R_(ii)—C(O)— or R_(ii)—OC(O)—, wherein R_(hh) and R_(ii) areeach independently one of the groups —[(B)_(m)—(Y—ONO₂)]_(s),—[(B)_(m′)—(Y′—ONO₂)]_(s′) or —[(B)_(m″)—(Y″—ONO₂)]_(s″) of formula (I)wherein m, m′ and m″ are 0 and Y, Y′ and Y″ are as below defined;in formula (IIt) d is an integer from 2 to 5, d′ is 0 or 1, with theproviso that d′ is 0 when d is an integer from 3 to 5, R_(t) is H,—C(O)—R_(tt) or —C(O)O—R_(tt) wherein R_(tt) is one of the groups—[(B)_(m)—(Y—ONO₂)]_(s), —[(B′)_(m′)—(Y′—ONO₂)]_(s′) or—[(B″)_(m″)—(Y″—ONO₂)]_(s″) of formula (I) wherein m, m′ and m″ are 0;in formula (IIu) a and b are each independently 0 or 1, R_(x) is H,—C(O)—R_(xx), —C(O)O—R_(xx)—, —C(O)NH—R_(xx) wherein R_(xx) is one ofthe groups —[(B)_(m)—(Y—ONO₂)]_(s), —[(B)_(m′)—(Y′—ONO₂)]_(s′) or—[(B)_(m″)—(Y″—ONO₂)]_(s″) of formula (I) wherein m, m′ and m″ are 0 andY, Y′ and Y″ are as below defined;Y, Y′ and Y″ of the groups (Y—ONO₂), —(Y′—ONO₂) and —(Y″—ONO₂) offormula (I) are bivalent radicals and they are each independentlyselected from:

A)

a straight or branched C₁-C₂₀ alkylene, preferably a straight orbranched C₂-C₁₀ alkylene

a straight or branched C₁-C₂₀ alkylene substituted with one or more—ONO₂ group(s), preferably a straight or branched C₂-C₁₀ alkylenesubstituted with a —ONO₂ group;

a cycloalkylene having 5 to 7 carbon atoms, the ring being optionallysubstituted with a straight or branched C₁-C₁₀ alkyl;

B)

wherein n⁰ is an integer from 0 to 20, preferably n⁰ is from 0 to 5,more preferably n⁰ is 0 or 1,n¹ is an integer from 1 to 20, preferably n¹ is an integer from 1 to 10,more preferably n¹ is an integer from 2 to 6;more preferably in formula (IB) and (IB′) n⁰ is 0 or 1 and n¹ is aninteger from 1 to 10;wherein in formulas (IB) and (IB′) the —ONO₂ group is linked to—(CH₂)_(n) ¹—;

C)

wherein:n¹ is an integer from 1 to 20, preferably n¹ is an integer from 1 to 10,or more preferably n¹ is an integer from 2 to 6,n² is an integer from 0 to 2, preferably n² is 1,R² is H or CH₃, preferably R² is CH₃,

X₁ is —OC(O)— or —C(O)O—;

more preferably in formula (IC) n¹ is an integer from 1 to 10, n² is 1and R² is CH₃, X₁ is —C(O)O—;wherein in formula (IC) the —ONO₂ group is linked to —(CH₂)_(n) ¹—;

D)

wherein in formula (ID):n¹ is an integer from 1 to 20, preferably n¹ is an integer from 1 to 10,or more preferably n¹ is an integer from 2 to 10, n², R² and X₁ are asdefined above;Y¹ is —CH₂—CH₂— or —CH═CH—(CH₂)_(n) ^(2a)— wherein n^(2a) is an integerfrom 0 to 5, preferably n^(2a) is 0,wherein in formula (ID) the —ONO₂ group is linked to —(CH₂)_(n) ¹—;preferably in formula (ID), n² is 1 and R² is CH₃, Y¹ is—CH═CH—(CH₂)_(n) ^(2a)— wherein n^(2a) is 0, X₁ is —C(O)O—, n¹ is aninteger from 1 to 10;

E)

wherein X₂ is —O—, —S—, —NH— or —N(CH₂CH₂OCH₃)—, preferably X₂ is —O— or—NH—,n³ is an integer from 1 to 5, preferably n³ is 1,n₃ is an integer from 0 to 10, preferably from 0 to 4, more preferablyn₃ is 0,n₄ an integer from 1 to 10, preferably from 1 to 4, more preferably n₄is 1preferably n₃ is 0 and n₄ is 1;n_(3′) is an integer from 0 to 10, preferably n_(3′) is from 0 to 4,n_(4′) is an integer from 1 to 10, preferably from 1 to 4,more preferably n_(3′) is 0 and n_(4′) is 1,R² is H or —CH₃, preferably R² is H,preferably in (IE) n³ is an integer from 1 to 5, n₃ is 0 and n₄ is from1 to 4, n_(3′) is 0 and n_(4′) is from 1 to 4, R² is H and X₂ is —O— or—NH—,more preferably in (IE) n³ is 1, n₃ is 0 and n₄ is 1, n_(3′) is 0 andn_(4′) is 1, R² is H and X₂ is —O— or —NH—,wherein in formula (IE) the —ONO₂ group is linked to the —(CH₂)_(n4′)group;

F)

wherein:n⁵ is an integer from 0 to 10, preferably n⁵ is 0 or 1;n⁶ is an integer from 1 to 10, preferably n⁶ is 1;R⁴, R⁵, R⁶, R⁷ are the same or different, and are H or straight orbranched C₁-C₄ alkyl, preferably R⁴, R⁵, R⁶, R⁷ are H;wherein in formula (IF) the —ONO₂ group is linked to

wherein n⁶ is as defined above;Y² is an heterocyclic saturated, unsaturated or aromatic 5 or 6 membersring, containing one or more heteroatoms selected from nitrogen, oxygen,sulfur,and is selected from the group consisting of:

G)

wherein n⁰ is an integer from 0 to 10,n⁷ is an integer from 1 to 10, preferably n⁷ is an integer from 1 to 6,more preferably n⁷ is 1;n⁸ is an integer from 0 to 10, preferably n⁸ is an integer from 0 to 6,more preferably n⁸ is 0;

R⁸ is CH₃ or CH₂ONO₂,

more preferably in formula (IG) n⁰ is 0, n⁷ is 1, n⁸ is 0 and R⁸ is CH₃or CH₂ONO₂,wherein in formula (IG) the —ONO₂ group is linked to the group

preferably Y and Y′ or Y″ are equal;preferred (Y—ONO₂), —(Y′—ONO₂) or —(Y″—ONO₂) groups are:

more preferably the groups (Y—ONO₂), —(Y′—ONO₂), and —(Y″—ONO₂) are eachindependently selected from:

with the proviso that in formula (I) s′ and s″ cannot be both 1 when:

-   -   A is the radical of formulas (IIb), (IId)-(IIr), or    -   A is the radical of formula (IIt) wherein d is from 3 to 5 and        d′ is 0, or    -   A is the radical of formula (IIu) wherein a is 0;        with the proviso that s′ and s″ can be both 1 when:    -   A is the radical of formulas (IIa), (IIc) or (IIs) and R_(a),        R_(c) and R_(s) are selected from:    -   R_(bx)—C(O)—S—CH₂—, R_(bx)—OC(O)—S—CH₂—, R_(bx)—NH—C(O)S—CH₂—        wherein R_(bx) is one of the groups —[(B)_(m)—(Y—ONO₂)]_(s),        —[(B)_(m′)—(Y′—ONO₂)]_(s′), or [(B)_(m″)—(Y″—ONO₂)]_(s″) wherein        m, m′ and m″, B, Y, Y′ and Y″ are as above defined;    -   R_(x)O—CH₂—, R_(x)O—CH(CH₃)—, (R_(x)O)-p-C₆H₄—CH₂—,        4-(R_(x)O)-3,5-diiodobenzyl-, 4-(R_(x)O)-3-nitrobenzyl- wherein        R_(x) is R_(xx)—C(O)—, R_(xx)—OC(O)— or R_(xx)—NHC(O)— wherein        R_(xx) is one of the groups —[(B)_(m)—(Y—ONO₂)]_(s),        [(B)_(m′)—(Y′—ONO₂)]_(s′) or —[(B)_(m″)—(Y″—ONO₂)]_(s″) wherein        m, m′ and m″, B, Y, Y′ and Y″ are as above defined;    -   R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—,        R_(g)C(O)(CH₂)₄—, wherein R_(g) is OH, (CH₃)₃CO—, R_(gx)—O—,        R_(gxx)—NH—, R_(gxx)—N(CH₃)— wherein R_(gx) and R_(gxx) are one        of the groups —[(B)_(m)—(Y—ONO₂)]_(s),        —[(B)_(m′)—(Y′—ONO₂)]_(s′) or —[(B)_(m″)—(Y″—ONO₂)]_(s″) wherein        m, m′ and m″, B, Y, Y′ and Y″ are as above defined;    -   R_(h)NH(CH₂)_(p)— or R_(i)NH(═NH)NH—(CH₂)₃—, wherein p is an        integer from 0 to 4, R_(h) is R_(hh)—C(O)— or R_(hh)—OC(O)—,        R_(i) is R_(ii)—C(O)— or R_(ii)—OC(O)—, wherein R_(hh) and        R_(ii) are one of the groups —[(B)_(m)—(Y—ONO₂)]_(s),        —[(B)_(m′)—(Y′—ONO₂)]_(s′) or —[(B)_(m″)—(Y″—ONO₂)]_(s″) wherein        m, m′ and m″, B, Y′ and Y″ are as above defined;    -   A is the radical of formula (IIt) wherein d′ is 1 and d is 2 and        R_(t) is —C(O)—R_(tt) or —C(O)O—R_(tt) wherein R_(tt) is one of        the groups —[(B)_(m)—(Y—ONO₂)]_(s), —[(B)_(m′)—(Y′—ONO₂)]_(s′),        or —[(B)_(m″)—(Y″—ONO₂)]_(s″) wherein m, m′ and m″ Y′ and Y″ are        as above defined;    -   A is the radical of formula (IIu) wherein a is 1 and R_(x) is        —C(O)—R_(xx), —C(O)O—R_(xx)— or —C(O)NH—R_(xx) wherein R_(xx) is        one of the groups —[(B)_(m)—(Y—ONO₂)]_(s),        —[(B)_(m′)—(Y′—ONO₂)]_(s′) or —[(B)_(m″)—(Y″—ONO₂)]_(s″) of        formula (I) wherein m, m′ and m″ B, Y′ and Y″ are as above        defined        with the proviso that the following compounds of formula (I) are        excluded:

-   3-(nitrooxy)propyl 2-(tert-butoxycarbonylamino)-4-phenyl butanoate,

-   3-(nitrooxy)propyl 2-amino-4-phenylbutanoate,

-   3-(nitrooxy)propyl 2-amino-4-phenylbutanoate hydrochloride,

-   4-(nitrooxy)butyl 2-(tert-butoxycarbonylamino)-4-phenylbutanoate,

-   4-(nitrooxy)butyl 2-amino-4-phenylbutanoate,

-   4-(nitrooxy)butyl 2-amino-4-phenylbutanoate hydrochloride,

-   (2-(nitrooxy)ethoxy)methyl 2-(tert-butoxycarbonylamino)-4-phenyl    butanoate,

-   (2-(nitrooxy)ethoxy)methyl 2-amino-4-phenylbutanoate,

-   (2-(nitrooxy)ethoxy)methyl 2-amino-4-phenyl butanoate hydrochloride,

-   1-tert-butyl 2-(4-(nitrooxy)butyl)pyrrolidine-1,2-dicarboxylate,

-   4-(nitrooxy)butyl pyrrolidine-2-carboxylate,

-   4-(nitrooxy)butyl pyrrolidine-2-carboxylate hydrochloride,

-   1-tert-butyl 2-(3-(nitrooxy)propyl)pyrrolidine-1,2-dicarboxylate,

-   3-(nitrooxy)propyl pyrrolidine-2-carboxylate,

-   3-(nitrooxy)propyl pyrrolidine-2-carboxylate hydrochloride.

Another embodiment relates to compounds of formula (I)

wherein s is 1 and m is 0, s′ and s″ are 0,A is selected from:

wherein

R₁ is H or —C(O)—OC(CH₃)₃,

R₂ is —C(O)OR_(2x), —C(O)NHR_(2x), —C(O)N(CH₃)R_(2x) and more preferablyR₂ is —C(O)OR_(2x) or —C(O)NHR_(2x), wherein R_(2x) is (Y—ONO₂) offormula (I) wherein Y is below reported,R_(a) of formula (IIa) is selected from:a) H, CH₃, isopropyl, isobutyl, sec-butyl, methylthio-(CH₂)₂—, benzyl,C₆H₅—CH₂—CH₂—, 3-triptophanyl-CH₂—, NH₂—CO—CH₂—, NH₂—CO—(CH₂)₂—,4-imidazolyl-CH₂—;

b) HS—CH₂—,

c) R_(x)O—CH₂—, R_(x)O—CH(CH₃)—, (R_(x)O)-p-C₆H₄—CH₂—, wherein R_(x) isH,d) R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—, wherein R_(g) is OH, (CH₃)₃CO—, orthe group R_(gg):

e) R_(h)NH(CH₂)_(p)— or R_(i)NH(═NH)NH—(CH₂)₃—, wherein p is an integerequal to 3 or 4, R_(h) is H or (CH₃)₃C—OC(O)—, R_(i) is H;R_(c) of formula (IIc) is selected from the group comprising:H, CH₃, isopropyl, isobutyl, sec-butyl, methylthio-(CH₂)₂—, benzyl,3-triptophanyl-CH₂, 4-imidazolyl-CH₂—, NH₂—CO—CH₂—, NH₂—CO—(CH₂)₂—;R_(L) of formula (IIl) is H,Y of the group (Y—ONO₂) is selected from:

A)

a straight or branched C₂-C₁₀ alkylene

a straight or branched C₂-C₁₀ alkylene substituted with a —ONO₂ group;

B)

wherein in formula (IB)n⁰ is from 0 to 5 and n¹ is an integer from 1 to 10;

C)

wherein in formula (IC)n¹ is an integer from 1 to 10,n² is 1 and R² is CH₃, X₁ is —C(O)O—;

D)

wherein in formula (ID):n² and R is CH₃,Y¹ is —CH═CH—(CH₂)_(n) ^(2a)— wherein n^(2a) is 0,X₁ is —C(O)O— and n¹ is an integer from 1 to 10;

E)

wherein in formula (IE)n³ is from 1 to 5,n₃ is 0 and n₄ is from 1 to 4,n_(3′) is 0 and n_(4′) is from 1 to 4,

X₂ is —O— or —NH—, R² is H,

preferably the group —(Y—ONO₂) is selected from:

the following are preferred compounds according to the presentinvention:

Another embodiment provides compounds of formula (I)

wherein s and m are 1,s′ and s″ are 0,B is selected from:

more preferably B is

A is a radical selected from:

wherein

R₁ is H or —C(O)O—C(CH₃)₃,

R₂ is —C(O)OR_(2x) wherein R_(2x) is the group —[(B)—(Y—ONO₂)] offormula (I) wherein B is as above defined and Y is below defined,R_(a) of formula (IIa) is selected from:a) H, CH₃, isopropyl, isobutyl, sec-butyl, methylthio-(CH₂)₂—, benzyl,C₆H₅—CH₂—CH₂—, 3-triptophanyl-CH₂—, NH₂—CO—CH₂—, NH₂—CO—(CH₂)₂—,4-imidazolyl-CH₂—;

b) HS—CH₂—;

c) R_(x)O—CH₂—, R_(x)O—CH(CH₃)— or (R_(x)O)-p-C₆H₄—CH₂—, wherein R_(x)is H;d) R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—, wherein R_(g) is OH or (CH₃)₃C—O—, orthe group R_(gg):

e) R_(h)NH(CH₂)_(p)— or R_(i)NH(═NH)NH—(CH₂)₃— wherein p is an integerequal to 3 or 4, R_(h) is H or (CH₃)₃C—OC(O)—, R_(i) is H;R_(L) of formula (IIl) is H;Y of the group —(Y—ONO₂) is selected from:

A)

a straight or branched C₂-C₁₀ alkylene,

a straight or branched C₂-C₁₀ alkylene substituted with a —ONO₂ group;

E)

wherein in formula (IE)n³ is from 1 to 5n₃ is 0 and n₄ is from 1 to 4,n_(3′) is 0 and n_(4′) is from 1 to 4,

X₂ is —O— or —NH—, R² is H;

preferably —(Y—ONO₂) is selected from:

The following are preferred compounds according to the presentinvention:

Another embodiment relates to compounds of formula (I)

wherein s is 1 and m is 0,s′ and s″ are 0,A is a radical selected from

wherein R₁ is —C(O)R_(1x), —C(O)OR_(1x) wherein R_(1x) is the group—(Y—ONO₂) of formula (I) wherein Y is below reported,R₂ in formulas (IIa) (IIc) and (IIl) is —C(O)OH, —C(O)—OC(CH₃)₃ or R₂ isthe group R₄:

R₃ in formula (IIs) is OH;R_(a) of formula (IIa) is selected from:a) H, CH₃, isopropyl, isobutyl, sec-butyl, methylthio-(CH₂)₂—, benzyl,C₆H₅—CH₂—CH₂—, 3-triptophanyl-CH₂—, NH₂—CO—CH₂—, NH₂—CO—(CH₂)₂—,4-imidazolyl-CH₂—;

b) HS—CH₂—;

c) R_(x)O—CH₂—, R_(x)O—CH(CH₃)—, (R_(x)O)-p-C₆H₄—CH₂— wherein R_(x) isH;d) R_(g)C(O)CH₂ or R_(g)C(O)(CH₂)₂—, wherein R_(g) is OH or (CH₃)₃C—O—,or R_(g) is the group R_(gg):

e) R_(h)NH(CH₂)_(p)— or R_(i)NH(═NH)NH—(CH₂)₃—, wherein p is an integerequal to 3 or 4, R_(h) is H or (CH₃)₃C—OC(O)—, R_(i) is H;R_(c) of formula (IIc) is selected from:H, CH₃, isopropyl, isobutyl, sec-butyl, methylthio—(CH₂)₂—, benzyl,3-triptophanyl-CH₂—, 4-imidazolyl-CH₂—, NH₂—CO—CH₂—, NH₂—CO—(CH₂)₂—;R_(L) of formula (IIl) is H;R_(s) of formula (IIs) is H, CH₃, isopropyl, isobutyl, sec-butyl,methylthio-(CH₂)₂—, benzyl, 3-triptophanyl-CH₂—, 4-imidazolyl-CH₂—,NH₂—CO—CH₂—, NH₂—CO—(CH₂)₂—;Y of the groups (Y—ONO₂ is selected from:

A)

a straight or branched C₂-C₁₀ alkylene

a straight or branched C₂-C₁₀ alkylene substituted with a —ONO₂ group;

B)

wherein in formula (IB)n⁰ is from 0 to 5 and n¹ is an integer from 1 to 10;

C)

wherein in formula (IC)n¹ is an integer from 1 to 10,n² is 1 and R² is CH₃, X₁ is —C(O)O—;

D)

wherein in formula (ID):n² is 1 and R² is CH₃,Y¹ is —CH═CH—(CH₂)_(n) ^(2a)— wherein n^(2a) is 0,X₁ is —C(O)O— and n¹ is an integer from 1 to 10;

E)

wherein in formula (IE)n³ is from 1 to 5,n₃ is 0 and n₄ is from 1 to 4,n_(3′) is 0 and n_(4′) is from 1 to 4,

X₂ is —O— or —NH—, R² is H,

preferably —(Y—ONO₂) is selected from:

the following are preferred compounds according to the presentinvention:

Another embodiment relates to compounds of formula (I)

wherein s and s′ are 1 and m, m′ are 0, s″ is 0,A is a radical of formula (IIa)

wherein R₁ is —C(O)R_(1x), or —C(O)OR_(1x) wherein R_(1x) is one of thegroups —(Y—ONO₂) or —(Y′—ONO₂) of formula (I) wherein Y and Y′ are belowreported,R₂ is —C(O)OH, —C(O)—OC(CH₃)₃ or R₂ is the group R₄:

R_(a) is selected from:b) R_(bx)C(O)—S—CH₂—, R_(bx)—OC(O)—S—CH₂—, R_(bx)—NH—C(O)S—CH₂— whereinR_(bx) is one of the groups —(Y—ONO₂) or —(Y′—ONO₂);c) R_(x)O—CH₂—, R_(x)O—CH(CH₃)—, (R_(x)O)-p-C₆H₄—CH₂—, wherein R_(x) isR_(xx)C(O)—, R_(xx)OC(O)— or R_(xx)NHC(O)— wherein R_(xx) is one of thegroups —(Y—ONO₂) or —(Y′—ONO₂) of formula (I) wherein Y and Y′ are belowdefined;d) R_(g)C(O)CH₂—, R_(g)C(O)(CH₂)₂—, wherein R_(g) is R_(gx)—O—,R_(gxx)—NH—, wherein R_(gx) and R_(gxx) are one of the groups —(Y—ONO₂)or —(Y′—ONO₂) of formula (I) wherein Y and Y′ are below defined;e) R_(h)NH(CH₂)_(p)— wherein p is an integer equal to 3 or 4, R_(h) isR_(hh)—C(O)— or R_(hh)—OC(O)— wherein R_(hh) is one of the groups—(Y—ONO₂) or —(Y′—ONO₂) of formula (I) wherein Y and Y′ are belowdefined, or R_(i)NH(═NH)NH—(CH₂)₃— wherein R_(i) is R_(ii)C(O)— orR_(ii)OC(O)— wherein R_(ii) is one of the groups —(Y—ONO₂) or —(Y′—ONO₂)of formula (I) wherein Y and Y′ are below defined;Y and Y′ of the groups (Y—ONO₂) and —(Y′—ONO₂) are each independentlyselected from:

A)

a straight or branched C₂-C₁₀ alkylene

a straight or branched C₂-C₁₀ alkylene substituted with a —ONO₂ group;

B)

wherein in formula (IB)n⁰ is from 0 to 5 and n¹ is an integer from 1 to 10;

C)

wherein in formula (IC)n¹ is an integer from 1 to 10,n² is 1 and R² is CH₃, X₁ is —C(O)O—;

D)

wherein in formula (ID):n² is 1 and R² is CH₃,Y¹ is —CH═CH—(CH₂)_(n) ^(2a)— wherein n^(2a) is 0,X₁ is —C(O)O— and n¹ is an integer from 1 to 10;

E)

wherein in formula (IE)n³ is from 1 to 5,n₃ is 0 and n₄ is from 1 to 4,n_(3′) is 0 and n_(4′) is from 1 to 4,

X₂ is —O— or —NH—, R² is H,

preferably (Y—ONO₂) and (Y′—ONO₂) are each independently selected from:

more preferably (Y—ONO₂) and (Y′—ONO₂) are equal.The following are preferred compounds according to the presentinvention:

Another embodiment provides compounds of formula (I)

wherein s is 1 and m is 0,s′ and s″ are 0,A is a radical of formula (IIa) or (IIl)

wherein R₁ is —C(O)R_(1x) or —C(O)OR_(1x) wherein R_(1x) is the group—(Y—ONO₂) of formula (I) wherein Y is below defined, R₂ in formulas(IIa) and (IIl) is the group R₄

R_(a) of formula (IIa) is selected from:a) H, CH₃, isopropyl, isobutyl, sec-butyl, methylthio-(CH₂)₂—, benzyl,C₆H₅—CH₂—CH₂—, 3-triptophanyl-CH₂—, NH₂—CO—CH₂—, NH₂—CO—(CH₂)₂—,4-imidazolyl-CH₂—;

b) HS—CH₂—;

c) R_(x)O—CH₂—, R_(x)O—CH(CH₃)—, (R_(x)O)-p-C₆H₄—CH₂—, wherein R_(x) isH;d) R_(g)C(O)CH₂ or R_(g)C(O)(CH₂)₂—, wherein R_(g) is OH, (CH₃)₃O— orthe

e) R_(h)NH(CH₂)_(p)— or R_(i)NH(═NH)NH—(CH₂)₃—, wherein p is an integerequal to 3 or 4, R_(h) is H or (CH₃)₃C—OC(O)—, R_(i) is H;R_(L) of formula (IIl) is H;Y of the group (Y—ONO₂) is selected from:

A)

a straight or branched C₂-C₁₀ alkylene

a straight or branched C₂-C₁₀ alkylene substituted with a —ONO₂ group;

B)

wherein in formula (IB)n⁰ is from 0 to 5 and n¹ is an integer from 1 to 10;

C)

wherein in formula (IC)n¹ is an integer from 1 to 10,n² is 1 and R² is CH₃, X₁ is —C(O)O—;

D)

wherein in formula (ID):n² is 1 and R² is CH₃,Y¹ is —CH═CH—(CH₂)_(n) ^(2a)— wherein n^(2a) is 0,X₁ is —C(O)O— and n¹ is an integer from 1 to 10;

E)

wherein in formula (IE)n³ is from 1 to 5,n₃ is 0 and n₄ is from 1 to 4,n_(3′) is 0 and n_(4′) is from 1 to 4,

X₂ is —O— or —NH—, R² is H,

preferably (Y—ONO₂) is selected from:

The following are preferred compounds according to the presentinvention:

Another embodiment relates to compounds of formula (I)

wherein s and s′ are 1 and m, m′ are 0, s″ is 0,A is a radical of formula (IIa) or (IIl)

whereinR₁ is —C(O)R_(1x), —C(O)OR_(1x) wherein R_(1x) is one of the groups—(Y—ONO₂) or —(Y′—ONO₂) of formula (I) wherein Y and Y′ are belowdefined;R₂ is —C(O)OR_(2x), —C(O)NHR_(2x), —C(O)N(CH₃)R_(2xx), wherein R_(2x)and R_(2xx) are one of the groups —(Y—ONO₂) or —(Y′—ONO₂) of formula (I)wherein Y and Y′ are below defined, more preferably R₂ is —C(O)OR_(2x)or —C(O)NHR_(2xx);R_(a) is selected from:a) H, CH₃, isopropyl, isobutyl, sec-butyl, methylthio—(CH₂)₂—, benzyl,C₆H₅—CH₂—CH₂—, 3-triptophanyl-CH₂—, NH₂—CO—CH₂—, NH₂—CO—(CH₂)₂—,4-imidazolyl-CH₂—;R_(L) in formula (IIl) is H;Y and Y′ of the groups (Y—ONO₂) and —(Y′—ONO₂) are each independentlyselected from:

A)

a straight or branched C₂-C₁₀ alkylene

a straight or branched C₂-C₁₀ alkylene substituted with a —ONO₂ group;

B)

wherein in formula (IB)n⁰ is from 0 to 5 and n¹ is an integer from 1 to 10;

C)

wherein in formula (IC)n¹ is an integer from 1 to 10,n² is 1 and R² is CH₃, X₁ is —C(O)O—;

D)

wherein in formula (ID):n² is 1 and R² is CH₃,Y¹ is —CH═CH—(CH₂)_(n) ^(2a)— wherein n^(2a) is 0,X₁ is —C(O)O— and n¹ is an integer from 1 to 10;

E)

wherein in formula (IE)n³ is from 1 to 5,n₃ is 0 and n₄ is from 1 to 4,n_(3′) is 0 and n_(4′) is from 1 to 4,

X₂ is —O— or —NH—, R² is H,

preferably (Y—ONO₂) and (Y′—ONO₂) are each independently selected from:

The following are preferred compounds according to the presentinvention:

Another embodiment relates to compounds of formula (I)

wherein s and s′ are 1, m is 1, m′ is 0, s″ is 0,B at each occurrence is independently selected from:

preferably B is

more preferably B is:

A is a radical of formula

whereinR₁ is —C(O)R_(1x), —C(O)OR_(1x) wherein R_(1x) is —(Y—ONO₂) of formula(I) wherein Y is below defined;R₂ is —C(O)OR_(2x), wherein R_(2x) is the group —[B—(Y′—ONO₂)] offormula (I) wherein B is as above reported and Y′ is below reported,R_(a) is selected from:H, CH₃, isopropyl, isobutyl, sec-butyl, methylthio—(CH₂)₂—, benzyl,C₆H₅—CH₂—CH₂—, 3-triptophanyl-CH₂—, NH₂—CO—CH₂—;NH₂—CO—(CH₂)₂—, 4-imidazolyl-CH₂—;R_(L) in formula (IIl) is H,Y and Y′ of the groups (Y—ONO₂) and —(Y′—ONO₂) are each independentlyselected from:

A)

a straight or branched C₂-C₁₀ alkylene

a straight or branched C₂-C₁₀ alkylene substituted with a —ONO₂ group;

E)

wherein in formula (IE)n³ is from 1 to 5,n₃ is 0 and n₄ is from 1 to 4,n_(3′) is 0 and n_(4′) is from 1 to 4, X₂ is —O— or —NH—,

R² is H,

preferably (Y—ONO₂) and —(Y′—ONO₂) are each independently selected from:

The following are preferred compounds according to the presentinvention:

Another embodiment relates to compounds of formula (I)

wherein s and s′ are 1, and s″ are 0, m and m′ are 0,A is a radical of formula

wherein R₁ is —C(O)R_(1x) or —C(O)OR_(1x) wherein R_(1x) is one of thegroups —(Y—ONO₂) or (Y′—ONO₂) of formula (I) wherein Y and Y′ are belowdefined;R₂ is —C(O)OR_(2x), —C(O)NHR_(2xx) or —C(O)N(CH₃)R_(2xx)r whereinR_(2xx) and R_(2x) are one of the groups —(Y—ONO₂) or —(Y′—ONO₂) offormula (I) wherein Y and Y′ are below defined, more preferably R₂ is—C(O)OR_(2x), —C(O)NHR_(2xx);R_(a) is selected from:

b) HS—CH₂—;

c) R_(x)O—CH₂—, R_(x)O—CH(CH₃)—, (R_(x)O)-p-C₆H₄—CH₂—, wherein R_(x) isH,d) R_(g)C(O)CH₂— or R_(g)C(O)(CH₂)₂—, wherein R_(g) is OH, (CH₃)₃CO—, orthe group R_(gg)

e) R_(h)NH(CH₂)_(p)— or R_(i)NH(═NH)NH—(CH₂)₃—, wherein p is an integerequal to 3 or 4, R_(h) is H, (CH₃)₃C—OC(O)—, R₂ is H;Y and Y′ of the groups (Y—ONO₂), —(Y′—ONO₂) are each independentlyselected from:

A)

a straight or branched C₂-C₁₀ alkylene

a straight or branched C₂-C₁₀ alkylene substituted with a —ONO₂ group;

E)

wherein in formula (IE)n³ is from 1 to 5,n₃ is 0 and n₄ is from 1 to 4,n_(3′) is 0 and n_(4′) is from 1 to 4,

X₂ is —O— or —NH—, R² is H,

preferably (Y—ONO₂) and (Y′—ONO₂) are each independently selected from:

The following are preferred compounds according to the presentinvention:

Another embodiment provides compounds of formula (I)

wherein s is 1 and m is 0, s′ and s″ are 0,A is a radical of formula

wherein R₁ is H or —C(O)O—C(CH₃)₃,R₂ is —C(O)OH or R₂ is equal to the group R₄

R_(a) is selected from:b) R_(bx)C(O)—S—CH₂—, R_(bx)OC(O)—S—CH₂—, R_(bx)NH—C(O)S—CH₂— whereinR_(bx) is the group —(Y—ONO₂) of formula (I) wherein Y is below defined,c) R_(x)O—CH₂—, R_(x)O—CH(CH₃)—, (R_(x)O)-p-C₆H₄—CH₂—, wherein R_(x) isR_(xx)C(O)—, R_(xx)OC(O)— or R_(xx)NHC(O)— wherein R_(xx) is the group—(Y—ONO₂) of formula (I) wherein Y is below defined;d) R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂— wherein R_(g) is R_(gx)O—,R_(gxx)—NH—, or Rg_(xx)—N(CH₃)—, wherein R_(gx) and R_(gxx) are thegroup —(Y—ONO₂) of formula (I) wherein Y is below defined, morepreferably R_(g) is R_(gx)O—, R_(gxx)—NH—e) R_(h)NH(CH₂)_(p)— wherein p is 3 or 4, and R_(h) is R_(hh)C(O)— orR_(hh)OC(O)— wherein R_(hh) is the group —(Y—ONO₂) of formula (I)wherein Y is below defined;or R_(i)NH(═NH)NH—(CH₂)₃— wherein R_(i) is R_(ii)C(O)— or R_(ii)OC(O)—wherein R_(ii) is the group —(Y—ONO₂) of formula (I) wherein Y is belowdefined;Y of the group (Y—ONO₂) is selected from:

A)

a straight or branched C₂-C₁₀ alkylene

a straight or branched C₂-C₁₀ alkylene substituted with a —ONO₂ group;

E)

wherein in formula (IE)n³ is from 1 to 5,n₃ is 0 and n₄ is from 1 to 4,n_(3′) is 0 and n_(4′) is from 1 to 4,

X₂ is —O— or —NH—, R² is H,

preferably (Y—ONO₂) is selected from:

The following are preferred compounds according to the presentinvention:

Another embodiment provides compounds of formula (I)

wherein s and s′ are 1 and m, m′ are 0, s″ is 0,A is a radical of formula

wherein R₁ is H or —C(O)O—C(CH₃)₃,R₂ is —C(O)OR_(2x), —C(O)NHR_(2xx), —C(O)N(CH₃)R_(2xx) wherein R_(2x)and R_(2xx) are one of the groups —(Y—ONO₂) or —(Y′—ONO₂) of formula (I)wherein Y and Y′ are below defined, more preferably R₂ is —C(O)OR_(2x),—C(O)NHR_(2x);R_(a) is selected from:b) R_(bx)C(O)—S—CH₂—, R_(bx)OC(O)—S—CH₂—, R_(bx)NH—C(O)S—CH₂— whereinR_(bx) is one of the groups —(Y—ONO₂) or —(Y′—ONO₂) wherein Y and Y′ arebelow defined;c) R_(x)O—CH₂—, R_(x)O—CH(CH₃)—, (R_(x)O)-p-C₆H₄—CH₂—, wherein R_(x) isR_(xx)C(O)—, R_(xx)OC(O)— or R_(xx)NHC(O)— wherein R_(xx) is one thegroups —(Y—ONO₂) or —(Y′—ONO₂) of formula (I) wherein Y and Y′ are belowreported;e) R_(h)NH(CH₂)_(p)— wherein p is 3 or 4, and R_(h) is R_(hh)C(O)— orR_(hh)OC(O)— wherein R_(hh) is one the groups —(Y—ONO₂) or —(Y′—ONO₂) offormula (I) wherein Y and Y′ are below reported;or R_(a) is R_(i)NH(═NH)NH—(CH₂)₃— wherein R_(i) is R_(ii)C(O)— orR_(ii)OC(O)— wherein R_(ii) is one the groups —(Y—ONO₂) or —(Y′—ONO₂) offormula (I) wherein Y and Y′ are below defined;Y and Y′ of the groups (Y—ONO₂) and —(Y′—ONO₂) are each independentlyselected from:

A)

a straight or branched C₂-C₁₀ alkylene

a straight or branched C₂-C₁₀ alkylene substituted with a —ONO₂ group;

E)

wherein in formula (IE)n³ is from 1 to 5,n₃ is 0 and n₄ is from 1 to 4,n_(3′) is 0 and n_(4′) is from 1 to 4,

X₂ is —O— or —NH—, R² is H,

preferably —(Y—ONO₂) and —(Y′—ONO₂) are each independently selectedfrom:

The following are preferred compounds according to the presentinvention:

Another embodiment provides compounds of formula (I)

wherein s and s′ are 1 and m, m′ are 0, s″ is 0,A is a radical of formula

wherein R₁ is H or —C(O)O—C(CH₃)₃,R₂ is —C(O)OR_(2x), —C(O)NHR_(2xx), —C(O)N(CH₃)R_(2xx) wherein R_(2x)and R_(2xx) are one of the groups —(Y—ONO₂) or —(Y′—ONO₂) of formula (I)wherein Y and Y′ are below defined, more preferably R₂ is —C(O)OR_(2x),—C(O)NHR_(2xx);R_(a) is selected from:d) R_(g)C(O)CH₂—, R_(g)C(O)(CH₂)₂—, wherein R_(g) is R_(gx)O—,R_(gxx)—NH—, R_(gxx)N(CH₃)—, wherein R_(gx) and R_(gxx) are one of thegroups —(Y—ONO₂) or —(Y′—ONO₂) of formula (I) wherein Y and Y′ are belowdefined, more preferably R_(g) is R_(gx)O— or R_(gxx)—NH—;Y and Y′ of the groups (Y—ONO₂) and —(Y′—ONO₂) are each independentlyselected from:

A)

a straight or branched C₂-C₁₀ alkylene

a straight or branched C₂-C₁₀ alkylene substituted with a —ONO₂ group;

E)

wherein in formula (IE)n³ is from 1 to 5,n₃ is 0 and n₄ is from 1 to 4,n_(3′) is 0 and n_(4′) is from 1 to 4,

X₂ is —O— or —NH—, R² is H,

preferably (Y—ONO₂) and (Y′—ONO₂) are each independently selected from:

The following are preferred compounds according to the presentinvention:

Another embodiment provides compounds of formula (I)

wherein s, s′ and s″ are 1, m, m′ and m″ are 0,A is a radical of formula

wherein R₁ is —C(O)R_(1x), —C(O)OR_(1x) wherein R_(1x) is one of thegroups —(Y—ONO₂) or —(Y′—ONO₂) or —(Y″—ONO₂) of formula (I) wherein Y,Y′ and Y″ are below defined;R₂ is —C(O)OR_(2x), —C(O)NHR_(2xx), —C(O)N(CH₃)R_(2xx) wherein R_(2x)and R_(2xx) are one of the groups —(Y—ONO₂) or —(Y′—ONO₂) or —(Y″—ONO₂)of formula (I) wherein Y, Y′ and Y″ are below reported, and morepreferably R₂ is —C(O)OR_(2x), —C(O)NHR_(2x);R_(a) is selected from:b) R_(bx)C(O)—S—CH₂—, R_(bx)OC(O)—S—CH₂—, R_(bx)NH—C(O)S—CH₂— whereinR_(bx) is one of the groups —(Y—ONO₂) or —(Y′—ONO₂) or —(Y″—ONO₂) offormula (I) wherein Y, Y′ and Y″ are below reported;c) R_(x)O—CH₂—, R_(x)O—CH(CH₃)—, (R_(x)O)-p-C₆H₄—CH₂—, wherein R_(x) isR_(xx)C(O)—, R_(xx)OC(O)— or R_(xx)NHC(O)— wherein R_(xx) is one of thegroups —(Y—ONO₂) or —(Y′—ONO₂) or —(Y″—ONO₂) of formula (I) wherein Y,Y′ and Y″ are below reported;d) R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—, wherein R_(g) is R_(gx)O—,R_(gxx)—NH—, R_(gxx)—N(CH₃)—, wherein R_(gx) and R_(gxx) are one of thegroups —(Y—ONO₂) or —(Y′—ONO₂) or —(Y″—ONO₂) of formula (I) wherein Y,Y′ and Y″ are below defined, more preferably R_(g) is R_(gx)O— orR_(gxx)NH—,e) R_(h)NH(CH₂)_(p)— wherein p is 3 or 4, and R_(h) is R_(hh)C(O)— orR_(hh)OC(O)— wherein R_(hh) is one of the groups —(Y—ONO₂) or —(Y′—ONO₂)or —(Y″—ONO₂) of formula (I) wherein Y, Y′ and Y″ are below defined,or R_(a) is R_(i)NH(═NH)NH—(CH₂)₃— wherein R_(i) is R_(ii)C(O)— orR_(ii)OC(O)— wherein R_(ii) is one of the groups —(Y—ONO₂) or —(Y′—ONO₂)or —(Y″—ONO₂) of formula (I) wherein Y, Y′ and Y″ are below reported;Y, Y′ and Y″ of the groups (Y—ONO₂), —(Y′—ONO₂) or —(Y″—ONO₂) are eachindependently selected from:

A)

a straight or branched C₂-C₁₀ alkylene

a straight or branched C₂-C₁₀ alkylene substituted with a —ONO₂ group;

E)

wherein in formula (IE)n³ is from 1 to 5,n₃ is 0 and n₄ is from 1 to 4,n_(3′) is 0 and n_(4′) is from 1 to 4,

X₂ is —O— or —NH—, R² is H,

preferably —(Y—ONO₂), —(Y′—ONO₂) and —(Y″—ONO₂) are each independentlyselected from:

The following are preferred compounds according to the presentinvention:

Another embodiment provides compounds of formula (I)

wherein s and s′ are 1, m and m′ are 0, s″ is 0,A is a radical of formula

wherein R₁ is H or —C(O)—OC(CH₃)₃;R₃ is —OC(O)R_(3x), OC(O)R_(3x), —C(O)—NHR_(3x), wherein R_(3x) is oneof the groups —(Y—ONO₂) or —(Y′—ONO₂) of formula (I) wherein Y and Y′are below defined;R_(s) is selected from:b″) R_(bx)—C(O)—S—CH₂—, R_(bx)—OC(O)—S—CH₂—, R_(bx)—NH—C(O)S—CH₂—wherein R_(bx) is one of the groups —(Y—ONO₂) or —(Y′—ONO₂) of formula(I) wherein Y and Y′ are below defined;c″) R_(x)O—CH₂—, R_(x)O—CH(CH₃)—, (R_(x)O)-p-C₆H₄—CH₂—, wherein R_(x) isR_(xx)C(O)—, R_(xx)OC(O)—, R_(xx)NHC(O)— wherein R_(xx) is one of thegroups —(Y—ONO₂) or —(Y′—ONO₂) of formula (I) wherein Y and Y′ are belowdefined;d″) R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—, wherein R_(g) is R_(gx)O— orR_(gxx)NH— wherein R_(gx) and R_(gxx) are one of the groups —(Y—ONO₂) or—(Y′—ONO₂) of formula (I) wherein Y and Y′ are below defined;e″) R_(h)NH(CH₂)_(p)— wherein p is 3 or 4 and R_(h) is R_(hh)C(O)— orR_(hh)OC(O)— wherein R_(hh) is one of the groups —(Y—ONO₂) or —(Y′—ONO₂)of formula (I) wherein Y and Y′ are below defined, orR_(i)NH(═NH)NH—(CH₂)₃—, wherein R_(i) is R_(ii)C(O)— or R_(ii)OC(O)—wherein R_(ii) is one of the groups —(Y—ONO₂) or —(Y′—ONO₂) of formula(I) wherein Y and Y′ are below defined;Y and Y′ of the groups (Y—ONO₂) and —(Y′—ONO₂) are each independentlyselected from:

A)

a straight or branched C₂-C₁₀ alkylene

a straight or branched C₂-C₁₀ alkylene substituted with a —ONO₂ group;

E)

wherein in formula (IE)n³ is from 1 to 5,n₃ is 0 and n₄ is from 1 to 4,n_(3′) is 0 and n_(4′) is from 1 to 4,

X₂ is —O— or —NH—, R² is H,

preferably (Y—ONO₂) and (Y′—ONO₂) are each independently selected from:

The following are preferred compounds according to the presentinvention:

Another embodiment provides compounds of formula (I)

wherein s is 1, m is 0, s′ and s″ are 0,A is a radical of formula

wherein R₁ is H or —C(O)—OC(CH₃)₃;R₃ is —OC(O)R_(3x), OC(O)OR_(3x), —OC(O)—NHR_(3x), wherein R^(3x) is thegroup —(Y—ONO₂) of formula (I) wherein Y is below reported;R_(s) is selected from:a″) H, CH₃, isopropyl, isobutyl, sec-butyl, methylthio-(CH₂)₂—, benzyl,C₆H₅—CH₂—CH₂—, 3-triptophanyl-CH₂—, NH₂—CO—CH₂—, NH₂—CO—(CH₂)₂—,4-imidazolyl-CH₂—;Y of the group (Y—ONO₂) is selected from:

A)

a straight or branched C₂-C₁₀ alkylene

a straight or branched C₂-C₁₀ alkylene substituted with a —ONO₂ group;

E)

wherein in formula (IE)n³ is from 1 to 5,n₃ is 0 and n₄ is from 1 to 4,n_(3′) is 0 and n_(4′) is from 1 to 4, X₂ is —O— or —NH—,

R² is H,

preferably (Y—ONO₂) is selected from:

The following are preferred compounds according to the presentinvention:

Another embodiment provides compounds of formula (I)

wherein s is 1 and m is 0, s′ and s″ are 0,A is a radical of formula (IIq)

R₁ is H or —C(O)O—C(CH₃)₃,

R₂ is —C(O)OR_(2x), —C(O)NHR_(2x)—C(O)N(CH₃) wherein R_(2x) is the group—(Y—ONO₂) of formula (I) wherein Y is below reported, more preferably R₂is —C(O)OR_(2x) or —C(O)NHR_(2x);Y of the group (Y—ONO₂) is selected from:

A)

a straight or branched C₂-C₁₀ alkylene

a straight or branched C₂-C₁₀ alkylene substituted with a —ONO₂ group;

wherein in formula (IE)n³ is from 1 to 5,n₃ is 0 and n₄ is from 1 to 4,n_(3′) is 0 and n_(4′) is from 1 to 4,

X₂ is —O— or —NH—, R² is H,

preferably and (Y—ONO₂) is selected from:

The following are preferred compounds according to the presentinvention:

Another embodiment relates to compounds of formula (I)

wherein s is 1 and m is 0, s′ and s″ are 0,A is a radical of formula (IIu)

wherein a is 1 and b is 0;

R₁ is H or —C(O)O—C(CH₃)₃,

R₂ is —C(O)OR_(2x), —C(O)NHR_(2x)—C(O)N(CH₃)R_(2x) wherein R_(2x) is thegroup —(Y—ONO₂) of formula (I) wherein Y is below reported, morepreferably R₂ is —C(O)OR_(2x), or —C(O)NHR_(2x),

R_(x) is H,

Y of the group (Y—ONO₂) is selected from:

A)

a straight or branched C₂-C₁₀ alkylene

a straight or branched C₂-C₁₀ alkylene substituted with a —ONO₂ group;

E)

wherein in formula (IE)n³ is from 1 to 5,n₃ is 0 and n₄ is from 1 to 4,n_(3′) is 0 and n_(4′) is from 1 to 4,

X₂ is —O— or —NH—, R² is H,

preferably (Y—ONO₂), is selected from:

The following are preferred compounds according to the presentinvention:

The compounds of the present invention show significant advantages overthe other known nitric oxide donor compounds, they release nitric oxide(NO) slower, they do not induce hypotension in normotensive subjects andmoreover they do not induce increasing of heart rate in hypertensivepatients.

The term “C₁-C₂₀ alkylene” as used herein refers to branched or straightchain C₁-C₂₀ hydrocarbon, preferably having from 1 to carbon atoms suchas methylene, ethylene, propylene, isopropylene, n-butylene, pentylene,n-hexylene and the like.

The term “C₁-C₁₀ alkyl” as used herein refers to branched or straightchain alkyl groups comprising one to ten carbon atoms, including methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl,octyl and the like.

The term “cycloalkylene” as used herein refers to ring having from 5 to7 carbon atoms including, but not limited to, cyclopentylene,cyclohexylene optionally substituted with side chains such as straightor branched (C₁-C₁₀)-alkyl, preferably CH₃.

The term “heterocyclic” as used herein refers to saturated, unsaturatedor aromatic 5 or 6 members ring, containing one or more heteroatomsselected from nitrogen, oxygen, sulphur, such as for example pyridine,pyrazine, pyrimidine, pyrrolidine, morpholine, imidazole and the like.

As stated above, the invention includes also the pharmaceuticallyacceptable salts of the compounds of formula (I) and stereoisomersthereof.

Examples of pharmaceutically acceptable salts are either those withinorganic bases, such as sodium, potassium, calcium and aluminiumhydroxides, or with organic bases, such as lysine, arginine,triethylamine, dibenzylamine, piperidine and other acceptable organicamines.

The compounds according to the present invention, when they contain inthe molecule one salifiable nitrogen atom, can be transformed into thecorresponding salts by reaction in an organic solvent such asacetonitrile, tetrahydrofuran with the corresponding organic orinorganic acids.

Examples of organic acids are: oxalic, tartaric, maleic, succinic,citric acids. Examples of inorganic acids are: nitric, hydrochloric,sulphuric, phosphoric acids. Salts with nitric acid are preferred.

The compounds of the invention which have one or more asymmetric carbonatoms can exist as optically pure enantiomers, pure diastereomers,enantiomers mixtures, diastereomers mixtures, enantiomer racemicmixtures, racemates or racemate mixtures. Within the object of theinvention are also all the possible isomers, stereoisomers and theirmixtures of the compounds of formula (I).

The invention also relates to the use of the compounds of formula (I) ortheir salts for treating cardiovascular diseases, inflammation, pain,fever, gastrointestinal disorders, ophthalmic diseases includingglaucoma, hepatic disorders, renal diseases, respiratory disorders,immunological diseases, bone metabolism dysfunctions, central andperipheral nervous system diseases, sexual dysfunctions, infectiousdiseases, for the inhibition of platelet aggregation and plateletadhesion, for treating pathological conditions resulting from abnormalcell proliferation and vascular diseases.

Another embodiment of the present invention relates to compositionscomprising at least a compound of formula (I) or its salt and at leastone therapeutic agent selected from anti-inflammatory drugs, drugs usedto treat cardiovascular diseases, drugs for treating ocular diseases,drugs for treating respiratory disorders.

Anti-inflammatory drugs include, but are not limited to, non steroidalanti-inflammatory drugs and steroidal anti-inflammatory drugs

Drugs used to treat cardiovascular diseases refers to any therapeuticcompound, or a pharmaceutically acceptable salt thereof, used to treatany cardiovascular disease. Suitable compounds include, but are notlimited to aspirin and derivatives thereof, anti-thrombotic drugs,angiotensin-converting enzyme inhibitors (ACE inhibitors),beta-adrenergic blockers, calcium channel blockers, angiotensin IIreceptor antagonists, endothelin antagonists, renin inhibitors,(β-adrenergic receptor agonists, cholesterol reducers such as, forexample, HMG-CoA reductase inhibitors, including, but not limited to,lovastatin, simvastatin, pravastatin, fluvastatin, cerivastatin,atorvastatin.

Drugs for treating ocular diseases include, but are not limited to,prostaglandins.

In another object of the invention the two components of the compositionabove defined are administered simultaneously or sequentially whereinthe two components may be administered by the same or differentadministration pathways.

Another object of the invention provide the use of the composition abovereported for the treatment of cardiovascular diseases, inflammation,pain, fever, gastrointestinal disorders, ophthalmic diseases includingglaucoma, hepatic disorders, renal diseases, respiratory disorders,immunological diseases, bone metabolism dysfunctions, central andperipheral nervous system diseases, sexual dysfunctions, infectiousdiseases, for the inhibition of platelet aggregation and plateletadhesion, for treating pathological conditions resulting from abnormalcell proliferation and vascular diseases.

Generally the treatment of cardiovascular disease and/or peripheralvascular disorders is a long-term therapy, and it is directed topatients suffering from cardiovascular disease and/or peripheralvascular disorders or inflammatory diseases which suffer fromhypertension or diabetes.

Long term treatment ranges from about one month to over two years ofchronic/maintenance administration.

Another object of the present invention relates to pharmaceuticalcompositions comprising the composition above reported and non toxicadjuvants and/or carriers usually employed in the pharmaceutical field.

An object of the present invention relates to pharmaceuticalcompositions comprising at least a compound of formula (I) together withnon toxic adjuvants and/or carriers usually employed in thepharmaceutical field.

The invention also relates to the use of the following compounds

-   3-(nitrooxy)propyl 2-(tert-butoxycarbonylamino)-4-phenyl butanoate,-   3-(nitrooxy)propyl 2-amino-4-phenylbutanoate,-   3-(nitrooxy)propyl 2-amino-4-phenylbutanoate hydrochloride,-   4-(nitrooxy)butyl 2-(tert-butoxycarbonylamino)-4-phenylbutanoate,-   4-(nitrooxy)butyl 2-amino-4-phenylbutanoate,-   4-(nitrooxy)butyl 2-amino-4-phenylbutanoate hydrochloride,-   (2-(nitrooxy)ethoxy)methyl 2-(tert-butoxycarbonylamino)-4-phenyl    butanoate,-   (2-(nitrooxy)ethoxy)methyl 2-amino-4-phenylbutanoate,-   (2-(nitrooxy)ethoxy)methyl 2-amino-4-phenyl butanoate hydrochloride,-   1-tert-butyl 2-(4-(nitrooxy)butyl)pyrrolidine-1,2-dicarboxylate-   4-(nitrooxy)butyl pyrrolidine-2-carboxylate,-   4-(nitrooxy)butyl pyrrolidine-2-carboxylate hydrochloride,-   1-tert-butyl 2-(3-(nitrooxy)propyl)pyrrolidine-1,2-dicarboxylate,-   3-(nitrooxy)propyl pyrrolidine-2-carboxylate,-   3-(nitrooxy)propyl pyrrolidine-2-carboxylate hydrochloride,    for treating cardiovascular diseases, inflammation, pain, fever,    gastrointestinal disorders, ophthalmic diseases including glaucoma,    hepatic disorders, renal diseases, respiratory disorders,    immunological diseases, bone metabolism dysfunctions, central and    peripheral nervous system diseases, sexual dysfunctions, infectious    diseases, for the inhibition of platelet aggregation and platelet    adhesion, for treating pathological conditions resulting from    abnormal cell proliferation and vascular diseases.

Another object of the present invention relates to compositionscomprising at least one of the following compounds:

-   3-(nitrooxy)propyl 2-(tert-butoxycarbonylamino)-4-phenyl butanoate,-   3-(nitrooxy)propyl 2-amino-4-phenylbutanoate,-   3-(nitrooxy)propyl 2-amino-4-phenylbutanoate hydrochloride,-   4-(nitrooxy)butyl 2-(tert-butoxycarbonylamino)-4-phenyl butanoate,-   4-(nitrooxy)butyl 2-amino-4-phenylbutanoate,-   4-(nitrooxy)butyl 2-amino-4-phenylbutanoate hydrochloride,-   (2-(nitrooxy)ethoxy)methyl 2-(tert-butoxycarbonylamino)-4-phenyl    butanoate,-   (2-(nitrooxy)ethoxy)methyl 2-amino-4-phenylbutanoate,-   (2-(nitrooxy)ethoxy)methyl 2-amino-4-phenyl butanoate hydrochloride,-   1-tert-butyl 2-(4-(nitrooxy)butyl)pyrrolidine-1,2-dicarboxylate,-   4-(nitrooxy)butyl pyrrolidine-2-carboxylate,-   4-(nitrooxy)butyl pyrrolidine-2-carboxylate hydrochloride,-   1-tert-butyl 2-(3-(nitrooxy)propyl)pyrrolidine-1,2-dicarboxylate,-   3-(nitrooxy)propyl pyrrolidine-2-carboxylate,-   3-(nitrooxy)propyl pyrrolidine-2-carboxylate hydrochloride,    and at least one therapeutic agent selected from anti-inflammatory    drugs, drugs used to treat cardiovascular diseases, drugs for    treating ocular diseases, drugs for treating respiratory disorders.

Anti-inflammatory drugs include, but are not limited to, non steroidalanti-inflammatory drugs and steroidal anti-inflammatory drugs

Drugs used to treat cardiovascular diseases refers to any therapeuticcompound, or a pharmaceutically acceptable salt thereof, used to treatany cardiovascular disease. Suitable compounds include, but are notlimited to aspirin and derivatives thereof, anti-thrombotic drugs,angiotensin-converting enzyme inhibitors (ACE inhibitors),beta-adrenergic blockers, calcium channel blockers, angiotensin IIreceptor antagonists, endothelin antagonists, renin inhibitors,β-adrenergic receptor agonists, cholesterol reducers such as, forexample, HMG-CoA reductase inhibitors, including, but not limited to,lovastatin, simvastatin, pravastatin, fluvastatin, cerivastatin,atorvastatin.

Drugs for treating ocular diseases include, but are not limited to,prostaglandins.

In another object of the invention the two components of the compositionabove defined are administered simultaneously or sequentially whereinthe two components may be administered by the same or differentadministration pathways.

Another object of the invention provides the use of the compositioncomprising at least one of the following compounds:

-   3-(nitrooxy)propyl 2-(tert-butoxycarbonylamino)-4-phenyl Butanoate,-   3-(nitrooxy)propyl 2-amino-4-phenylbutanoate,-   3-(nitrooxy)propyl 2-amino-4-phenylbutanoate hydrochloride,-   4-(nitrooxy)butyl 2-(tert-butoxycarbonylamino)-4-phenyl butanoate,-   4-(nitrooxy)butyl 2-amino-4-phenylbutanoate,-   4-(nitrooxy)butyl 2-amino-4-phenylbutanoate hydrochloride,-   (2-(nitrooxy)ethoxy)methyl 2-(tert-butoxycarbonylamino)-4-phenyl    butanoate,-   (2-(nitrooxy)ethoxy)methyl 2-amino-4-phenylbutanoate,-   (2-(nitrooxy)ethoxy)methyl 2-amino-4-phenyl butanoate hydrochloride,-   1-tert-butyl 2-(4-(nitrooxy)butyl)pyrrolidine-1,2-dicarboxylate,-   4-(nitrooxy)butyl pyrrolidine-2-carboxylate,-   4-(nitrooxy)butyl pyrrolidine-2-carboxylate hydrochloride,-   1-tert-butyl 2-(3-(nitrooxy)propyl)pyrrolidine-1,2-dicarboxylate,-   3-(nitrooxy)propyl pyrrolidine-2-carboxylate,-   3-(nitrooxy)propyl pyrrolidine-2-carboxylate hydrochloride    and at least one therapeutic agent selected from anti-inflammatory    drugs, drugs used to treat cardiovascular diseases, drugs for    treating ocular diseases, drugs for treating respiratory disorders,    for the treatment of cardiovascular diseases, inflammation, pain,    fever, gastrointestinal disorders, ophthalmic diseases including    glaucoma, hepatic disorders, renal diseases, respiratory disorders,    immunological diseases, bone metabolism dysfunctions, central and    peripheral nervous system diseases, sexual dysfunctions, infectious    diseases, for the inhibition of platelet aggregation and platelet    adhesion, for treating pathological conditions resulting from    abnormal cell proliferation and vascular diseases.

An object of the present invention relates to pharmaceuticalcompositions comprising the composition above reported together with nontoxic adjuvants and/or carriers usually employed in the pharmaceuticalfield.

The daily dose of the active ingredient that should be administered canbe a single dose or it can be an effective amount divided into severalsmaller doses that are to be administered throughout the day. The dosageregimen and administration frequency for treating the mentioned diseaseswith the compound of the invention and/or with the pharmaceuticalcompositions of the present invention will be selected in accordancewith a variety of factors, including for example age, body weight, sexand medical condition of the patient as well as severity of the disease,route of administration, pharmacological considerations and eventualconcomitant therapy with other drugs. In some instances, dosage levelsbelow or above the aforesaid range and/or more frequent may be adequate,and this logically will be within the judgment of the physician and willdepend on the disease state.

The compounds of the invention may be administered orally, parenterally,rectally or topically, by inhalation or aerosol, in formulationseventually containing conventional non-toxic pharmaceutically acceptablecarriers, adjuvants and vehicles as desired. Topical administration mayalso involve the use of transdermal administration such as transdermalpatches or iontophoresis devices. The term “parenteral” as used herein,includes subcutaneous injections, intravenous, intramuscular,intrasternal injection or infusion techniques.

Injectable preparations, for example sterile injectable aqueous oroleaginous suspensions may be formulated according to known art usingsuitable dispersing or wetting agents and suspending agents. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally acceptable diluent or solvent.Among the acceptable vehicles and solvents are water, Ringer's solutionand isotonic sodium chloride. In addition, sterile, fixed oils areconventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed including synthetic mono ordiglycerides, in addition fatty acids such as oleic acid find use in thepreparation of injectables.

Suppositories for rectal administration of the drug can be prepared bymixing the active ingredient with a suitable non-irritating excipient,such as cocoa butter and polyethylene glycols.

Solid dosage forms for oral administration may include capsules,tablets, pills, powders, granules and gels. In such solid dosage forms,the active compound may be admixed with at least one inert diluent suchas sucrose, lactose or starch. Such dosage forms may also comprise, asin normal practice, additional substances other than inert diluents,e.g. lubricating agents such as magnesium stearate. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. Tablets and pills can additionally be prepared withenteric coatings.

Liquid dosage forms for oral administration may include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups and elixirscontaining inert diluents commonly used in the art, such as water. Suchcompositions may also comprise adjuvants, such as wetting agents,emulsifying and suspending agents, and sweetening, flavouring and thelike.

Synthesis Procedure

1. The Compounds of General Formula (I)

wherein:s is equal to 1;m, m′, m″, s′ and s″ are 0Y is as above defined,A is a radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and(IIn) wherein R₁ is —C(O)—R_(1x) and it binds the group —Y—ONO₂, R₂ is—COOH;in formula (IIn) R_(n) is —C(O)—R_(nx), or is —(CH₂)₂—NH—R_(h) whereinR_(h) is —C(O)—R_(hh) and it binds the group —Y—ONO₂R_(a) of formula (IIa) is selected in group a)R_(c) of formula (IIc) is selected in group a′)in formula (IIt) d is an integer from 3 to 5, d′ is 0;can be prepared as follows

1a) by reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″,Y, Y′, Y″ are as above defined in 1, A is a radical of formula(IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein R₂ is—C(O)OC(CH₃)₃; R₁, R_(a), R_(c), R_(h), R^(n), d, and d′ are as definedin 1, with anhydrous or aqueous organic or inorganic acid to hydrolyzethe t-butyl ester following procedure well known in the literature.

1b) by reacting a compound of formula A with a compound of formula(IIIa)

A+HOOC—Y—ONO₂  (IIIa)

wherein Y is as above defined and A is selected from (IIa)-(IIm),(IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein R₁ is —H and R₂ is—C(O)O(CH₃)₃;in formula (IIn) R_(n) is H, or is —(CH₂)₂—NH—R_(h) wherein R_(h) is H;R_(a) of formula (IIa) is selected in group a);R_(c) of formula (IIc) is selected in group a′);in formula (IIt) d and d′ are as above defined;in the presence of a condensing agent such as dicyclohexylcarbodiimide(DCC) or N,N′-carbonyldiimidazol (CDI) or other known condensingreagents such as O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU), in the presence or not of1-Hydroxybenzotriazole (HOBT) in solvent such as DMF, THF, chloroform ata temperature in the range from −5° C. to 80° C. in the presence or notof a base as for example DMAP.

The nitric acid ester compounds of formula (IIIa) can be obtained fromthe corresponding alcohols of formula HOOC—Y—OH (IIIb), that arecommercially available, by reaction with nitric acid and aceticanhydride in a temperature range from −51° C. to 0° C. or reacting thecorresponding halogen derivatives of formula HOOC—Y—Hal (IIIc) whereinHal is an halogen atom preferably Cl, Br, I, that are commerciallyavailable, with AgNO₃ as known in the literature. Alternatively thereaction with AgNO₃ can be performed under microwave irradiation insolvents such acetonitrile or THF at temperatures in the range betweenabout 100-180° C. for time range about 1-60 min.

Dinitrated compounds of formula (IIIa) can be also directly preparedwith 12 and AgNO₃ starting from carboxylic acids with a double bond inthe chain as described in WO 2005/070868.

Compounds (IIIa) can be also prepared from the corresponding Tosylderivative (IIId) HOOC—Y—OTs by reacting with AgNO₃ or MetalNO₃ whereinMetal is Li⁺, Na⁺, K⁺, in solvents such acetonitrile or DMF at refluxingtemperature or under microwave irradiation at temperatures in the rangebetween about 100-180° C. for time range about 1-120 min.

1b′) alternatively compound A reported in 1b) can be reacted with acompound of formula (IIIe):

A+Act-CO—Y—ONO₂  (IIIe)

wherein Y is as above defined; Act is an Halogen atom or a carboxylicacid activating group used in peptide chemistry such as:

the reaction is generally carried out in presence of a inorganic ororganic base in an aprotic polar/non-polar solvent such as DMF, THF orCH₂Cl₂ at temperatures range between 0°-80° C. or in a double phasesystem H₂O/Et₂O at temperatures range between 20°-40° C.; or in thepresence of DMAP and a Lewis acid such as Sc(OTf)₃ or Bi(OTf)₃ insolvents such as DMF, CH₂Cl₂.

The compounds of formula (IIIe) can be obtained as described in WO2006/008196.

1c) compounds A reported in 1b) are commercially available or can beprepared by reacting a compound of formula A₁ wherein A₁ is a radical offormula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein R₂ is—COOH, R₁ and R_(n) are substituted by the Fmoc protective group andR_(a), R_(c), d and d′ are as defined in 1, with tert-butyl alcohol andsulphuric acid or other methods to obtain a tert-butyl ester well knownin the literature. Eventually removing the Fmoc protective group usingmethods known in the literature.

Compounds A₁ are commercially available or can be prepared by thecorrespondent compounds A₂:

A₂→A₁

wherein A₂ is a radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu)and (IIn) wherein R₂ is —COOH, and R₁ is —C(O)OC(CH₃)₃, R_(n) is—C(O)OC(CH₃)₃ or is —(CH₂)₂—NH—C(O)OC(CH₃)₃, R_(a), R_(c) d and d′ areas defined in 1, by converting the —BOC protective group into the Fmocprotective group as described in the literature.

Compounds A₂ are commercially available.

2. Alternatively compounds of formula (I) described in 1. can beobtained:

2a) by reacting a compound of formula (IVa)

A-(Y—X)  (IVa)

wherein X is an halogen atom or tosyl group, Y is as above defined and Ais as above defined in 1b), with AgNO₂ or MetalNO₂ as above described in1b).

Compounds (IVa) can be obtained by reacting compound A as above definedin 1b), with compounds (IIIc) as above described in 1b), with acondensing reagent such as DCC or CDI as above described in 1b);

or

2a′) alternatively compounds of formula (I) described in 1a) can beobtained by reacting a compound of formula (Va):

A-(Y—OH)  (Va)

wherein A and Y are as above defined in 1a), with triflicanhydride/tetraalkylammonium nitrate salt in an aprotic polar/non-polarsolvent such as DMF, THF or CH₂Cl₂ at temperatures range between −78° to80° C.

Compounds (Va) can be obtained by reacting compound A as defined in 1b),with compounds (IIIb) with a condensing reagent as above described for(IIIa) in 1b).

3. The compounds of general formula (I) wherein:

s is equal to 1;m, m′, m″, s′ and s″ are 0Y is as above defined,A is a radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and(IIn) wherein R₁ is —C(O)O—R_(1x) and it binds the group —Y—ONO₂, R₂ is—COOH;in formula (IIn) R_(n) is —C(O)O—R_(nx) or —(CH₃)₃—NH—R_(h)wherein R_(h) is —C(O)O—R_(hh), and it binds the group —Y—ONO₂R_(a) of formula (IIa) is selected in group a)R_(c) of formula (IIc) is selected in group a′)in formula (IIt) d is an integer from 3 to 5, d′ is 0;can be prepared as follows

3a) by reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″,Y, Y′, Y″ are as above defined in 3, A is a radical of formula(IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein R₂ is—C(O)OC(CH₃)₃; R₁, R_(a), R_(c) R_(n), R_(h), d and d′ are as defined in3. with anhydrous or aqueous organic or inorganic acid to hydrolyze thet-butyl ester following procedure well known in the literature.

3b) by reacting a compound of formula A with a compound of formula(IIIf)

A+Act-(O)C—O—Y—ONO₂  (IIIf)

wherein A is as above reported in 1b), Y is as above reported and Act isas above defined in 1b′).

The reaction is generally carried out in presence of a inorganic ororganic base in an aprotic polar/non-polar solvent such as DMF, THF orCH₂Cl₂ at temperatures range between 0°-80° C. or in a double phasesystem H₂O/Et₂O at temperatures range between 20°-40° C.; or in thepresence of DMAP and a Lewis acid such as Sc(OTf)₃ or Bi(OTf)₃ insolvents such as DMF, CH₂Cl₂. Compounds (IIIf) are obtained as describedin WO 2006/008196.

4. The compounds of general formula (I) wherein:

s and m are equal to 1;s′, s″, m′, m″ are equal to 0;Y is as above defined;

B is:

A is a radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and(IIn) wherein R₁ is —H and R₂ is —C(O)OR_(2x) and binds the group—B—Y—ONO₂in formula (IIn) R₁ is —H or is —(CH₃)₂—NH₂;R_(a) of formula (IIa) is selected in group a),R_(c) of formula (IIc) is selected in group a′),in formula (IIt) d is an integer from 3 to 5, d′ is 0;can be obtained as follows:

4a) reacting a compound of formula (I) wherein B, s, s′, s″, m, m′, m″,Y, Y′ and Y″ are as above defined in 4, A is a radical of formula(IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein R₂, R_(a),R_(c), d and d′ are as defined in 4, R₁ is —C(O)OC(CH₃)₃; R_(n) is—C(O)OC(CH₃)₃ or is —(CH₃)₃—NH—C(O)OC(CH₃)₃;

with anhydrous or aqueous organic or inorganic acid as well known in theliterature to remove all the —BOC protective groups.

4b) by reacting a compound of formula A with compounds of formula (IIIg)

A+Hal-W₁—C(O)O—Y—ONO₂  (IIIg)

wherein Y is as above described, Hal is an halogen atom and W₁ is —CH₂—or —CH(CH₃)—, and A is a compound of formula (IIa)-(IIm), (IIo)-(IIr),(IIt)-(IIu) and (IIn) wherein R₁ is —C(O)OC(CH₃)₃ and R₂ is —COOH;R_(a) of formula (IIa) is selected in group a),R_(c) of formula (IIc) is selected in group a′),in formula (IIt) d and d′ are as above defined;in formula (IIn) R_(n) is —C(O)OC(CH₃)₃ or is —(CH₃)₃—NH—C(O)OC(CH₃)₃;in the presence of a inorganic or organic base in an aproticpolar/non-polar solvent such as DMF, THF or CH₂Cl₂ at temperatures rangebetween 0° to 100° C. or in a double phase system H₂O/Et₂O attemperatures range between 20° to 40° C. Compounds A as above definedare commercially available.

The compounds of formula (IIIg) are obtained by reacting thecommercially available haloalkylhalocarbonate of formula (IIIh)

Hal-W₁—OC(O)Hal  (IIIh)

wherein Hal and W₁ are as above defined, with a compound of formula(IIIi)

HO—Y—ONO₂  (IIIi)

wherein Y is as above defined, in the presence of a inorganic or organicbase in an aprotic polar or in an aprotic non-polar solvent such as DMF,THF or CH₂Cl₂ at temperatures range between 0° to 80° C.

Dinitrated compounds of formula (IIIi) can be also prepared with I₂ andAgNO₃ or by Sharpless oxidation and then Nitration with Acetic anhydrideand nitric acid starting from a double bond in the chain as described inWO 2005/070868.

The compounds of formula (IIIi) are obtained by reacting compounds offormula HO—Y—Hal (IIIj) wherein Y and Hal are as above defined orcompounds of formula HO—Y—OTs (IIIk) wherein Ts is the tosyl group, withAgNO₃ on MetalNO₃ in a suitable organic solvent such as acetonitrile ortetrahydrofuran (THF) under nitrogen in the dark at temperatures rangebetween 20°-80° C.; alternatively the reaction with AgNO₃ or MetalNO₃can be performed under microwave irradiation in solvents suchacetonitrile or THF at temperatures in the range between about 100-180°C. for time range about 1-120 min as already described in 1b)

The compounds of formula (IIIj) and (IIIk) are commercially available orcan be obtained from commercially available compounds HO—Y—OH (IIIl)with methods well known in the literature.

5. Alternatively compounds (I) described in 4a) can be obtained

5a) by reacting compounds of formula (VIa) wherein A, B and Y have beenalready defined in 4. with tetraalkylammonium nitrate and triflicanhydride as previously described

A-(B)—(Y—OH)  (VIa)

Compounds (VIa) can be obtained by reacting compounds A as defined in4b) with compounds (IIIm):

Hal-W₁—OC(O)O—Y—OH  (IIIm)

Using the same procedure described in 4b). Compounds (IIIm) are preparedfrom commercially available compounds Hal-W₁—OC(O)Hal (IIIh) by reactingwith compounds HO—Y—OH (IIIl) in the presence of a inorganic or organicbase in an aprotic polar or in an aprotic non-polar solvent such as DMF,THF or CH₂Cl₂ at temperatures range between 0° to 80° C., using a ratio(IIIh)/(IIIl) 1:1.

6. The compounds of general formula (I) wherein:

s and m are equal to 1;s′, s″, m′, m″ are equal to 0;Y is as above defined;

B is:

A is a radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and(IIn) wherein R₁ is —H and R₂ is —C(O)OR_(2x) and binds the group

—B—Y—ONO₂

in formula (IIn) R_(n) is —H or is —(CH₂)₂—NH₂;R_(a) of formula (IIa) is selected in group a)R_(c) of formula (IIc) is selected in group a′),in formula (IIt) d is an integer from 3 to 5, d′ is 0;can be obtained as follows:

6a) reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″, Y,Y′ and Y″ are as above defined in 6, A is a radical of formula(IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein R₂, R_(a), andR_(c), d and d′ are as defined in 6, R₁ or R_(n) is —C(O)OC(CH₃)₃ or—(CH₂)₂—NH—C(O)OC(CH₃)₃; with anhydrous or aqueous organic or inorganicacid as well known in the literature to remove all the —BOC protectivegroups.

6b) by reacting a compound of formula A with compounds of formula (IIIn)

A+Hal-W₁—OC(O)—Y—ONO₂  (IIIn)

wherein Y is as above described, Hal is an halogen atom and W₁ is —CH₂—or —CH(CH₃)—, and A is a compound of formula (IIa)-(IIm), (IIo)-(IIr),(IIt)-(IIu) and (IIn) wherein R₁ is —C(O)OC(CH₃)₃ and R₂ is —COOH;R_(a) of formula (IIa) is selected in group a),R_(c) of formula (IIc) is selected in group a′),in formula (IIn) R_(n) is —C(O)OC(CH₃)₃ or is —(CH₂)₂—NHR_(h) whereinR_(h) is —C(O)OC(CH₃)₃;in formula (IIt) d is an integer from 3 to 5, d′ is 0;in the presence of a inorganic or organic base in an aproticpolar/non-polar solvent such as DMF, THF or CH₂Cl₂ at temperatures rangebetween 0° to 100° C. or in a double phase system H₂O/Et₂O attemperatures range between 20° to 40° C.

The compounds of formula (IIIn) are obtained by reacting a compoundW₂—CHO, wherein W₂ is H—, CH₃— with compounds of formula (IIIe), whereinY and Act are as above defined, and ZnCl₂ as described in the literature(Steven K. Davidsen and al., J. Med. Chem., 37(26), 4423, 1994).

W₂—CHO+ZnCl₂+Act-(O)C—Y—ONO₂  (IIIe)

7. The compounds of general formula (I) wherein:

s is equal to 1;s′, s″, m, m′, m″ are equal to 0;Y is as above defined;A is a radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and(IIn) wherein R₁ is —H and R₂ is —C(O)NHR_(2xx) or —C(O)N(CH₃)R_(2xx)and R₂ binds the group —Y—ONO₂in formula (IIn) R_(n) is —H or is —(CH₂)₂—NH₂;R_(a) of formula (IIa) is selected in group a);R_(c) of formula (IIc) is selected in group a′);in formula (IIt) d is an integer from 3 to 5, d′ is 0;can be obtained as follows:

7a) reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″, Y,Y′ and Y″ are as above defined in 7, A is a radical of formula(IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein R₂, R_(a) R_(c),d and d′ are as defined in 7, R₁ is —C(O)OC(CH₃)₃; R_(n) is—C(O)OC(CH₃)₃ or is —(CH₂)₂—NHR_(h) wherein R_(h) is —C(O)OC(CH₃)₃;

with anhydrous or aqueous organic or inorganic acid as well known in theliterature to remove all the —BOC protective groups.

7b) by reacting a compound of formula A with compounds of formula (IIIo)

W₃NH—Y—ONO₂  (IIIo)

wherein Y is as above described, W₃ is H or —CH₃, A has been alreadydefined in 4b), in the presence of a condensing agent likedicyclohexylcarbodiimide (DCC) or N,N′-carbonyldiimidazol (CDI) or otherknown condensing reagents such asO-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU), in the presence or not of1-Hydroxybenzotriazole (HOBT) in solvent such as DMF, THF, chloroform ata temperature in the range from −5° C. to 60° C. in the presence or notof a base as for example DMAP. Compounds (IIIo) can be prepared fromcompounds (IIIA), wherein Y and W₃ are as above defined by hydrolysingthe BOC protecting group as known in the literature:

(CH₃)₃CO(O)C—NW₃—Y—ONO₂  (IIIP)

Compounds (IIIA) can be prepared from compounds (IIIq) or (IIIr) whereinW₃, Y, Hal and Ts are as above described, by reacting with AgNO₂ asalready described for analogous compounds:

(CH₃)₃CO(O)C—NW₂—Y—Hal  (IIIq)

(CH₃)₃CO(O)C—NW₃—Y—OTs  (IIIr)

Alternatively compounds (IIIA) can be prepared from compounds (IIIs) byreacting with tetraalkylammonium nitrate as already described foranalogous compounds.

(CH₃)₃CO(O)C—NW₂—Y—OH  (IIIs)

Compounds (IIIq) and (IIIr) can be prepared from compounds (IIIs) byhalogenation or tosylation as known in the literature. Compounds (IIIs)are obtained by known methods from compounds (IIIt) that arecommercially available.

W₃NH—Y—OH  (IIIt)

8. The compounds of general formula (I) wherein:

s is equal to 1;s′, s″, m, m′, m″ are equal to 0;Y is as above defined;

A is a radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and(IIn) wherein R₁ is —H and R₂ is —C(O)OR_(2x) and binds the group—Y—ONO₂

in formula (IIn) R_(n) is —H or is —(CH₂)₂—NH₂;R_(a) of formula (IIa) is selected in group a);R_(c) of formula (IIc) is selected in group a′);in formula (IIt) d is an integer from 3 to 5, d′ is 0;can be obtained as follows:

8a) reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″, Y,Y′ and Y″ are as above defined in 8, A is a radical of formula(IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein R₂, R_(a) R_(c)d and d′ are as defined in 8, R₁, is —C(O)OC(CH₃)₃; R_(n) is—C(O)OC(CH₃)₃ or is —(CH₂)₂—NHR—C(O)OC(CH₃)₃;

with anhydrous or aqueous organic or inorganic acid as well known in theliterature to remove all the —BOC protective groups.

8b) by reacting a compound of formula A with compounds of formula (IIIi)

HO—Y—ONO₂  (IIIi)

wherein Y is as above described, A is a radical of formula (IIa)-(IIm),(IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein R₁ is —C(O)OC(CH₃)₃; R₂ is—COOH or is equal to R_(2a) wherein R_(2a) is the group —COAct whereinAct is as above described in 1b′) and is a carboxylic acid activatinggroup, R_(a) R_(c) d and d′ are as defined in 8, R_(n) is —C(O)OC(CH₃)₃or is —(CH₂)₂—NHR—C(O)OC(CH₃)₃;in the presence of a condensing agent such as dicyclohexylcarbodiimide(DCC) or N,N′-carbonyldiimidazol (CDI) or other known condensingreagents such as O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU), in the presence or not of1-Hydroxybenzotriazole (HOBT) in solvent such as DMF, THF, chloroform ata temperature in the range from −5° C. to 60° C. in the presence or notof a base as for example DMAP when R₂ is —COOH; or in the presence ofequimolar amount of DMAPin solvent such as DMF, THF, chloroform at a temperature in the rangefrom −5° C. to 60° C. when R₂ is equal to R_(2a).

9. Alternatively the compounds of formula (I) as defined in 8a) can beobtained as follow:

9a) reacting a compound of formula (IVb)

A-Y—X  (IVb)

wherein Y is as above defined and A is as above defined in 8a) and X isan halogen atom or a tosyl group, by reacting with AgNO₂ or MetalNO₂ asabove described. Compounds (IVb) can be obtained by reacting compound Adefined as above in 6b), with compounds (IIIj) or (IIIk)

HO—Y—Hal  (IIIj)

HO—Y—OTs  (IIIk)

with a condensing reagent such as DCC or CDI or HATU as above defined in6b).

10. Alternatively the compounds of formula (I) as defined in 8a) can beobtained

10a) by reacting a compound of formula (Vb)

A-Y—OH  (Vb)

wherein Y is as above defined, and A is as already defined in 8a) withtriflic anhydride/tetraalkylammonium nitrate as already described.Compounds (Vb) can be obtained by reacting compounds A as abovedescribed in 8b) with a compound of formula HO—Y—OH (IIIl) with acondensing reagent such as DCC or CDI or HATU as above defined in 8b)using a ratio A/(IIIl) 1:1.

11. The compounds of general formula (I) wherein:

s and s′ are equal to 1;s″, m, m′, m″, are 0Y, Y′ can be equal or different and are as above defined,A is selected from (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn)wherein:R₁ is —C(O)—R_(1x) and binds the group —Y—ONO₂, R₂ is —C(O)OR_(2x) andbinds the group —Y′—ONO₂;in formula (IIn) R_(n) is —C(O)—R_(nx) or —(CH₂)₂—NH—R_(h)wherein R_(h) is —C(O)—R_(hh), R^(n) or R_(h) binds the group —Y—ONO₂;R_(a) of formula (IIa) is selected in group a);R_(c) of formula (IIc) is selected in group a′);in formula (IIt) d is an integer from 3 to 5, d′ is 0;can be prepared as follows:

11a) by reacting compounds of formula (I) as defined in 1, obtained withthe procedure described in 1. with compounds (IIIi)

Wherein Y and Y′ are equal or different and are as above defined and Ahas the following meanings:A is a radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and(IIn) wherein R₁ is —C(O)—R_(1x) and binds the group —Y—ONO₂, R₂ is—COOH;in formula (IIn) R_(n) is —C(O)—R_(nx) or —(CH₂)₂—NH—R_(h)wherein R_(h) is —C(O)—R_(hh), R_(n) or R_(h) binds the group —Y—ONO₂;R_(a) of formula (IIa) is selected in group a);R_(c) of formula (IIc) is selected in group a′);in formula (IIt) d is an integer from 3 to 5, d′ is 0;using the same procedure described in 8b).

12. The compounds of general formula (I) wherein:

s and s′ are equal to 1;s″, m, m′, m″, are 0Y, Y′ can be equal or different and are as above defined,A is a radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and(IIn) wherein R₁ is —C(O)O—R_(1x) and binds the group —Y—ONO₂, R₂ is—C(O)OR_(2x) and R₂ binds the group —Y′—ONO₂;in formula (IIn) R_(n) is —C(O)O—R_(nx) or —(CH₂)₂—NH—R_(h)wherein R_(h) is —C(O)O—R_(hh), R_(n) or R_(h) binds the group —Y—ONO₂;R_(a) of formula (IIa) is selected in group a),R_(c) of formula (IIc) is selected in group a′);in formula (IIt) d is an integer from 3 to 5, d′ is 0;can be prepared as follows:

12a) by reacting compounds of formula (I) obtained with the proceduredescribed in 3. with compounds (IIIi)

Wherein Y and Y′ are equal or different and are as above defined and Ahas the following meanings:A is a radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and(IIn) wherein R₁ is —C(O)O—R_(1x) and binds the group —Y—ONO₂, R₂ is—COOH;in formula (IIn) R_(n) is —C(O)O—R_(nx) or —(CH₂)₂—NH—R_(h)wherein R_(h) is —C(O)O—R_(hh), R_(n) or R_(h) binds the group —Y—ONO₂;R_(a) of formula (IIa) is selected in group a);R_(c) of formula (IIc) is selected in group a′);in formula (IIt) d is an integer from 3 to 5, d′ is 0;using the same procedure described in 8b).

13. The compounds of general formula (I) wherein:

s and s′ are equal to 1;s″, m, m′, m″, are 0Y, Y′ can be equal or different and are as above defined,A is selected from (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn)wherein:R₁ is —C(O)—R_(1x) and binds the group —Y—ONO₂, R₂ is —C(O)NHR_(2xx) or—C(O)N(CH₃)R_(2xx) and binds the group —Y′—ONO₂;in formula (IIn) R_(n) is —C(O)—R_(nx) or —(CH₂)₂—NH—R_(h)wherein R_(h) is —C(O)—R_(hh), R_(n), or R_(h) binds the group —Y—ONO₂;R_(a) of formula (IIa) is selected in group a);R_(c) of formula (IIc) is selected in group a′);in formula (IIt) d is an integer from 3 to 5, d′ is 0;can be prepared as follows:

13a) by reacting compounds of formula (I) obtained with the proceduredescribed in 1. with compounds (IIIo)

Wherein Y and Y′ are equal or different and are as above defined, W₃ isas above defined and A has the following meanings:A is a radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and(IIn) wherein R₁ is —C(O)—R_(1x) and binds the group —Y—ONO₂, R₂ is—COOH;in formula (IIn) R_(n) is —C(O)—R_(nx) or —(CH₂)₂—NH—R_(h)wherein R_(h) is —C(O)—R_(hh), R_(n), or R_(h) binds the group —Y—ONO₂;R_(a) of formula (IIa) is selected in group a);R_(c) of formula (IIc) is selected in group a′);in formula (IIt) d is an integer from 3 to 5, d′ is 0;using the same procedure described in 7b).

14. The compounds of general formula (I) wherein:

s and s′ are equal to 1;s″, m, m′, m″, are 0Y, Y′ can be equal or different and are as above defined,A is a radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and(IIn) wherein R₁ is —C(O)O—R_(1x) and R₁ binds the group —Y—ONO₂, R₂ is—C(O)NHR_(2xx) or —C(O)N(CH₃)R_(2xx) and R₂ binds the group —Y′—ONO₂;in formula (IIn) R_(n) is —C(O)O—R_(nx) or —(CH₂)₂—NH—R_(h)wherein R_(h) is —C(O)O—R_(hh), R_(n), or R_(h) binds the group —Y—ONO₂;R_(a) of formula (IIa) is selected in group a),R_(c) of formula (IIc) is selected in group a′);in formula (IIt) d is an integer from 3 to 5, d′ is 0;can be prepared as follows:

14a) by reacting compounds of formula (I) obtained with the proceduredescribed in 3. with compounds (IIIo)

Wherein Y and Y′ are equal or different and are as above defined, W₃ isas above defined and A has the following meanings:A is a radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and(IIn) wherein R₁ is —C(O)O—R_(1x) and binds the group —Y—ONO₂, R₂ is—COOH;in formula (IIn) R_(n) is —C(O)O—R_(nx) or —(CH₂)₂—NH—R_(h)wherein R_(h) is —C(O)O—R_(hh), R_(n), or R_(h) binds the group —Y—ONO₂;R_(a) of formula (IIa) is selected in group a);R_(c) of formula (IIc) is selected in group a′);in formula (IIt) d is an integer from 3 to 5, d′ is 0;using the same procedure described in 7b).

15. The compounds of general formula (I) wherein:

s, s′ and m′ are equal to 1;s″, m, m″, are 0Y, Y′ can be equal or different and are as above defined;

B is:

A is selected from (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn)wherein:R₁ is —C(O)—R_(1x) and binds the group —Y—ONO₂, R₂ is —C(O)OR_(2x) andR₂ binds the group —B—Y′—ONO₂;in formula (IIn) R_(n) is —C(O)—R_(nx) or —(CH₂)₂—NH—R_(h)wherein R_(h) is —C(O)—R_(hh), R_(n), or R_(h) binds the group —Y—ONO₂;R_(a) of formula (IIa) is selected in group a),R_(c) of formula (IIc) is selected in group a′),in formula (IIt) d is an integer from 3 to 5, d′ is 0;can be prepared as follows:

15a) By reacting compounds of formula (I) obtained with the proceduredescribed in 1. with compounds (IIIg)

A-Y—ONO₂+Hal-W₁—OC(O)O—Y—ONO₂  (IIIg)

wherein Y is as above described, Hal is an halogen atom and W₁ is —CH₂—or —CH(CH₃)—, and A has the following meanings:A is a radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and(IIn) wherein R₁ is —C(O)—R_(1x)— and binds the group —Y—ONO₂, R₂ is—COOH;in formula (IIn) R_(n) is —C(O)—R_(nx) or —(CH₂)₂—NH—R_(h)wherein R_(h) is —C(O)—R_(hh), R_(n), or R_(h) binds the group —Y—ONO₂;R_(a) of formula (IIa) is selected in group a);R_(c) of formula (IIc) is selected in group a′),in formula (IIt) d is an integer from 3 to 5, d′ is 0;using the same procedure described in 4b).

16. The compounds of general formula (I) wherein:

s, s′ and m′ are equal to 1;s″, m, m″, are 0Y, Y′ can be equal or different and are as above defined;

B is:

A is selected from (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn)wherein:R₁ is —C(O)—R_(1x) and binds the group —Y—ONO₂, R₂ is —C(O)OR_(2x) andbinds the group —B—Y′—ONO₂;in formula (IIn) R_(n) is —C(O)—R_(nx) or —(CH₂)₂—NH—R_(h)wherein R_(h) is —C(O)—R_(hh), R_(n), or R_(h) binds the group —Y—ONO₂;R_(a) of formula (IIa) is selected in group a),R_(c) of formula (IIc) is selected in group a′),in formula (IIt) d is an integer from 3 to 5, d′ is 0;can be prepared as follows:

16a) by reacting compounds of formula (I) obtained with the proceduredescribed in 1. with compounds (IIIn)

wherein Y is as above described, Hal is an halogen atom and W₁ is —CH₂—or —CH(CH₃)—, and A has the following meanings:A is a radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and(IIn) wherein R₁ is —C(O)—R_(1x)— and binds the group —Y—ONO₂, R₂ is—COOH;in formula (IIn) R_(n) is —C(O)—R_(nx) or —(CH₂)₂—NH—R_(h)wherein R_(h) is —C(O)—R_(hh), R_(n), or R_(h) binds the group —Y—ONO₂;R_(a) of formula (IIa) is selected in group a);R_(c) of formula (IIc) is selected in group a′);in formula (IIt) d is an integer from 3 to 5, d′ is 0;using the same procedure described in 6b).

17. The compounds of general formula wherein:

s, s′ and m′ are equal to 1;s″, m, m″, are 0Y, Y′ can be equal or different and are as above defined;

B is:

A is a radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and(IIn) wherein R₁ is —C(O)O—R_(1x) and R₂ is —C(O)OR_(2x) and R₁ bindsthe group —Y—ONO₂ and R₂ binds the group —B—Y′—ONO₂;in formula (IIn) R_(n) is —C(O)O—R_(nx) or —(CH₂)₂—NH—R_(h)wherein R_(h) is —C(O)O—R_(hh), R_(n), or R_(h) binds the group —Y—ONO₂;R_(a) of formula (IIa) is selected in group a),R_(c) of formula (IIc) is selected in group a′)in formula (IIt) d is an integer from 3 to 5, d′ is 0;can be prepared as follows:

17a) by reacting compounds of formula (I) obtained with the proceduredescribed in 3. with compounds (IIIg)

wherein Y is as above described, Hal is an halogen atom and W₁ is —CH₂—or —CH(CH₃)—, and A has the following meanings:A is a radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and(IIn) wherein R₁ is —C(O)O—R_(1x)— and binds the group —Y—ONO₂,

R₂ is —COOH;

in formula (IIn) R_(n) is —C(O)O—R_(nx), or is —(CH₂)₂—NH—R_(h) whereinR_(h) is —C(O)O—R_(hh), R_(n), or R_(h) binds the group —Y—ONO₂;R_(a) of formula (IIa) is selected in group a);R_(c) of formula (IIc) is selected in group a′),in formula (IIt) d is an integer from 3 to 5, d′ is 0;using the same procedure described in 4b).

18. The compounds of general formula (I) wherein:

s, s′ and m′ are equal to 1;s″, m, m″, are 0Y, Y′ can be equal or different and are as above defined;

B is:

A is a radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and(IIn) wherein R₁ is —C(O)O—R_(1x) and R₂ is —C(O)OR_(2x) and R₁ bindsthe group —Y—ONO₂ and R₂ binds the group —B—Y′—ONO₂;in formula (IIn) R_(n) is —C(O)O—R_(nx) or —(CH₂)₂—NH—R_(h) whereinR_(h) is —C(O)O—R_(hh), R_(n), or R_(h) binds the group —Y—ONO₂;R_(a) of formula (IIa) is selected in group a),R_(c) of formula (IIc) is selected in group a′);in formula (IIt) d is an integer from 3 to 5, d′ is 0;can be prepared as follows:

18a) By reacting compounds of formula (I) obtained with the proceduredescribed in 3. with compounds (IIIn)

wherein Y is as above described, Hal is an halogen atom and W₁ is —CH₂—or —CH(CH₃)—, and A has the following meanings:A is a radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and(IIn) wherein R₁ is —C(O)O—R_(1x)— and binds the group —Y—ONO₂, R₂ is—COOH;in formula (IIn) R_(n) is —C(O)O—R_(nx), or is —(CH₂)₂—NH—R_(h) whereinR_(h) is —C(O)O—R_(hh), R_(n), or R_(h) binds the group —Y—ONO₂;R_(a) of formula (IIa) is selected in group a);R_(c) of formula (IIc) is selected in group a′);in formula (IIt) d is an integer from 3 to 5, d′ is 0;using the same procedure described in 6b).

19. Alternatively the compounds of general formula (I) described inprocedure 11. wherein:

s and s′ are equal to 1;s″, m, m′, m″, are 0Y, Y′ can be equal or different and are as above defined,A is a radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and(IIn) wherein R₁ is —C(O)—R_(1x) and R₂ is —C(O)OR_(2x) and R₂ binds thegroup —Y—ONO₂ and R₁ binds the group —Y′—ONO₂;in formula (IIn) R_(n) is —C(O)—R_(nx), or is —(CH₂)₂—NH—R_(h), whereinR_(h) is —C(O)—R_(hh), R_(n), or R_(h) binds the group —Y′—ONO₂;R_(a) of formula (IIa) is selected in group a),R_(c) of formula (IIc) is selected in group a′);in formula (IIt) d is an integer from 3 to 5, d′ is 0;can be prepared as follows:

19a) By reacting compounds of formula (I) obtained with the proceduredescribed in 8. with compounds (IIIa) or (IIIe)

Wherein Y and Y′ are equal or different and are as above defined, Act isas above defined and A has the following meanings:A is a radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and(IIn) wherein R₂ is —C(O)OR_(2x) and binds the group —Y—ONO₂, R₁ is —H;in formula (IIn) R_(n) is —H or is —(CH₂)₂—NH₂;R_(a) of formula (IIa) is selected in group a);R_(c) of formula (IIc) is selected in group a′);in formula (IIt) d is an integer from 3 to 5, d′ is 0;using the same procedure described in 1b) or 1b′).

20. Alternatively the compounds of general formula (I) described inprocedure 12, wherein:

s and s′ are equal to 1;s″, m, m′, m″, are 0Y, Y′ can be equal or different and are as above defined,A is selected from (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn)wherein:R₁ is —C(O)O—R_(1x) and R₂ is —C(O)OR_(2x) and R₂ binds the group—Y—ONO₂ and R₁ binds the group —Y′—ONO₂;in formula (IIn) R_(n) is —C(O)O—R_(nx) or —(CH₂)₂—NH—R_(h)wherein R_(h) is —C(O)O—R_(hh), R_(n), or R_(h) binds the group—Y′—ONO₂;R_(a) of formula (IIa) is selected in group a),R_(c) of formula (IIc) is selected in group a′);in formula (IIt) d is an integer from 3 to 5, d′ is 0;can be prepared as follows:

20a) By reacting compounds of formula (I) obtained with the proceduredescribed in 8. with compounds (IIIf)

Wherein Y and Y′ are equal or different and are as above defined and Ahas the following meanings:A is a radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and(IIn) wherein R₂ is —C(O)OR_(2x) and binds the group —Y—ONO₂, R₁ is —H;in formula (IIn) R_(n) is —H or is —(CH₂)₂—NH₂;R_(a) of formula (IIa) is selected in group a);R_(c) of formula (IIc) is selected in group a′),in formula (IIt) d is an integer from 3 to 5, d′ is 0;using the same procedure described in 3b).

21. Alternatively the compounds of general formula (I) described inprocedure 13. wherein:

s and s′ are equal to 1;s″, m, m′, m″, are 0Y, Y′ can be equal or different and are as above defined,A is selected from (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn)wherein:R₁ is —C(O)—R_(1x) and R₂ is —C(O)NHR_(2xx) or —C(O)NCH₃—R_(2xx) and R₂binds the group —Y—ONO₂ and R₁ binds the group —Y′—ONO₂;in formula (IIn) R_(n) is —C(O)—R_(nx), or is —(CH₂)₂—NH—R_(h) whereinR_(h) is —C(O)—R_(hh), R_(n), or R_(h) binds the group —Y′—ONO₂;R_(a) of formula (IIa) is selected in group a),R_(c) of formula (IIc) is selected in group a′);in formula (IIt) d is an integer from 3 to 5, d′ is 0;can be prepared as follows:

21a) By reacting compounds of formula (I) obtained with the proceduredescribed in 7. with compounds (IIIa) or (IIIe)

wherein Y and Y′ are equal or different and are as above defined, Act isas above defined and A has the following meanings:A is a radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and(IIn) wherein R₂ is —C(O)NHR_(2xx) or —C(O)N(CH₃)R_(2xx) and binds thegroup —Y—ONO₂, R₁ is —H;in formula (IIn) R_(n) is —H or is —(CH₂)₂—NH₂;R_(a) of formula (IIa) is selected in group a);R_(c) of formula (IIc) is selected in group a′);in formula (IIt) d is an integer from 3 to 5, d′ is 0;using the same procedure described in 1b) or 1b′).

22. Alternatively the compounds of general formula (I) wherein:

s and s′ are equal to 1;s″, m, m′, m″, are 0, Y, Y′ can be equal or different and are as abovedefined,A is a radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and(IIn) wherein R₁ is —C(O)O—R_(1x) and R₂ is —C(O)NHR_(2xx) or—C(O)N(CH₃)R_(2xx) and R₂ binds the group —Y—ONO₂ and R₁ binds the group—Y′—ONO₂;in formula (IIn) R_(n) is —C(O)O—R_(n), or —(CH₂)₂—NH—R_(h)wherein R_(h) is —C(O)O—R_(hh), R_(n), or R_(h) binds the group—Y′—ONO₂;R_(a) of formula (IIa) is selected in group a),R_(c) of formula (IIc) is selected in group a′)in formula (IIt) d is an integer from 3 to 5, d′ is 0;can be prepared as follows:

22a) By reacting compounds of formula (I) obtained with the proceduredescribed in 7. with compounds (IIIf)

wherein Y and Y′ are equal or different and are as above defined and Ahas the following meanings:A is a radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and(IIn) wherein R₂ is —C(O)NHR_(2xx) or —C(O)N(CH₃)R_(2xx) and binds thegroup —Y—ONO₂, R₁ is —H;in formula (IIn) R_(n) is —H or is —(CH₂)₂—NH₂;R_(a) of formula (IIa) is selected in group a);R_(c) of formula (IIc) is selected in group a′),in formula (IIt) d is an integer from 3 to 5, d′ is 0;using the same procedure described in 3b).

23. Alternatively the compounds of general formula (I) wherein:

s, s′ and m are equal to 1;s″, m′, m″, are 0Y, Y′ can be equal or different and are as above defined;

B is:

A is selected from (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn)wherein:R₁ is —C(O)—R_(1x) and R₂ is —C(O)OR_(2x) and R₂ binds the group—B—Y—ONO₂ and R₁ binds the group —Y′—ONO₂;in formula (IIn) R_(n) is —C(O)—R_(nx), or is —(CH₂)₂—NH—R_(h) whereinR_(h) is —C(O)—R_(hh), R_(n), or R_(h) binds the group —Y′—ONO₂;R_(a) of formula (IIa) is selected in group a),R_(c) of formula (IIc) is selected in group a′),in formula (IIt) d is an integer from 3 to 5, d′ is 0;can be prepared as follows:

23a) By reacting compounds of formula (I) obtained with the proceduredescribed in 4. or 6. with compounds (IIIa) or (IIIe)

wherein Y, and Y′ are equal or different and are as above defined, Actand B are as above described and A has the following meanings:A is a radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and(IIn) wherein R₁ is —H, R₂ is —C(O)OR_(2x) and R₂ binds the group—B—Y—ONO₂in formula (IIn) R_(n) is —H or is —(CH₂)₂—NH₂;R_(a) of formula (IIa) is selected in group a);R_(c) of formula (IIc) is selected in group a′),in formula (IIt) d is an integer from 3 to 5, d′ is 0;using the same procedure described in 1b) or 1b′).

24. Alternatively the compounds of general formula (I) wherein:

s, s′ and m are equal to 1;s″, m′, m″, are 0Y, Y′ can be equal or different and are as above defined;

B is:

A is a radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and(IIn) wherein R₁ is —C(O)O—R_(1x) and R₂ is —C(O)OR_(2x) and R₂ bindsthe group —B—Y—ONO₂ and R₁ binds the group —Y′—ONO₂;in formula (IIn) R_(n) is —C(O)O—R_(nx) or —(CH₂)₂—NH—R_(h)wherein R_(h) is —C(O)O—R_(hh), R_(n), or R_(h) binds the group—Y′—ONO₂;R_(a) of formula (IIa) is selected in group a),R_(c) of formula (IIc) is selected in group a′);in formula (IIt) d is an integer from 3 to 5, d′ is 0;can be prepared as follows:

24a) by reacting compounds of formula (I) obtained with the proceduredescribed in 4. or 6. depending on the meanings of B with compounds(IIIf)

wherein Y, and Y′ are equal or different and are as above defined, Actis as above described and A has the following meanings:A is a radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and(IIn) wherein R₁ is —H, R₂ is —C(O)OR_(2x) and binds the group —B—Y—ONO₂

B is:

in formula (IIn) R_(n) is —H or is —(CH₂)₂—NH₂;R_(a) of formula (IIa) is selected in group a);R_(c) of formula (IIc) is selected in group a′),in formula (IIt) d is an integer from 3 to 5, d′ is 0;using the same procedure described in 3b).

25. The compounds of general formula (I) wherein:

s, is equal to 1;s′ s″, m, m′, m″, are 0Y is as above defined;A is a radical of formula (IIs) wherein R₁ is —C(O)—R_(1x) and it bindsthe group —Y—ONO₂, R₃ is —OH and R_(s) is selected in group a″), can beprepared as follows

25a) by reacting compounds of formula A with a compound of formula(IIIa) or (IIIe):

HOOC—Y—ONO₂  (IIIa)

ActOC—Y—ONO₂  (IIIe)

wherein Y is as above defined, Act is as above described and A is acompound of formula (IIs) wherein R₁ is —H, R₃ is —OH and R_(s) isselected in group a″), using the same procedure described in 1b) or 1b′)using a ratio A/(IIIa) or A/(IIIe) 1:1.

Compounds A are commercially available.

26. The compounds of general formula (I) wherein:

s is equal to 1;s′, s″, m, m′, m″, are 0Y is as above defined;A is a radical of formula (IIs) wherein R₁ is —C(O)O—R_(1x) and it bindsthe group —Y—ONO₂, R₃ is —OH and R_(s) is selected in groupa″), can be prepared as follows:

26a) by reacting compounds of formula A with a compound of formula(IIIf):

Act-(O)C—O—Y—ONO₂  (IIIf)

wherein Y is as above defined, Act is as above described and A is acompound of formula (IIs) described in 25a) wherein R₁ is —H, R₃ is —OHand R_(s) is selected in group a″), using the same procedure describedin 3b) using a ratio A/(IIIf) 1:1.

27. The compounds of general formula (I) wherein:

s is equal to 1;s′, s″, m, m′, m″, are 0Y is as above defined;A is a radical of formula (IIs) wherein R₃ is —OC(O)—R_(3x) and it bindsthe group —Y—ONO₂; R₁ is —H and R_(s) is selected in group a″), can beprepared as follows:

27a) by reacting compounds of formula (I) wherein s, s′, s″, m, m′, m″,Y, Y′, Y″ are as above defined in 27, A is a radical of formula (IIs) R₁is —C(O)OC(CH₃)₃; R₃, and R_(s) are as defined in 27; with anhydrous oraqueous organic or inorganic acid to hydrolyze the —BOC protectivegroups following procedure well known in the literature.

27b) by reacting a compound of formula A with a compound of formula(IIIe)

Act-(O)C—Y—ONO₂  (IIIe)

wherein Y and Act are as above defined; A is a compound of formula (IIs)wherein R₁ is —C(O)OC(CH₃)₃, R₃ is —OH and R_(s) is selected in groupa″), using the same procedure described in 1b′). Compounds A arecommercially available.

28. The compounds of general formula (I) wherein:

s is equal to 1;s′, s″, m, m′, m″, are 0Y is as above defined;A is a radical of formula (IIs) wherein R₃ is —OC(O)O—R_(3x) and itbinds the group —Y—ONO₂; R₁ is —H and R₁ is selected in group a″), canbe prepared as follows:

28a) by reacting compounds of formula (I) wherein s, s′, s″, m, m′, m″,Y, Y′, Y″ are as above defined in 28, A is a radical of formula (IIs) R₁is —C(O)OC(CH₃)₃; R₃ and R_(s) are as defined in 28. with anhydrous oraqueous organic or inorganic acid to hydrolyze the —BOC protectivegroups following procedure well known in the literature.

28b) By reacting a compound of formula A with a compound of formula(IIIf)

Act-(O)C—O—Y—ONO₂  (IIIf)

wherein Y and Act are as above defined; A is a compound of formula (IIs)described in 27a) wherein R₁ is —C(O)OC(CH₃)₃, R₃ is —OH and R_(s) isselected in group a″), using the same procedure described in 3b)

29. The compounds of general formula (I) wherein:

s is equal to 1;s′, s″, m, m′, m″, are 0Y is as above defined;A is a radical of formula (IIs) wherein R₃ is —OC(O)—NH—R_(3x)— and itbinds the group —Y—ONO₂; R₁ is —H and R_(s) is selected in group a″),can be prepared as follows:

29a) by reacting compounds of formula (I) wherein s, s′, s″, m, m′, m″,Y, Y′, Y″ are as above defined in 29, A is a radical of formula (IIs) R₁is —C(O)OC(CH₃)₃; R₃ and R_(s) are as defined in 29. with anhydrous oraqueous organic or inorganic acid to hydrolyze the —BOC protectivegroups following procedure well known in the literature.

29b) by reacting a compound of formula A with a compound of formula(IIIu)

Act-(O)C—NH—Y—ONO₂  (IIIu)

wherein Y and Act are as above defined; A is a compound of formula (IIs)described in 27b) wherein R₁ is —C(O)OC(CH₃)₃, R₃ is —OH and R₁ isselected in group a″), in the presence of a inorganic or organic base inan aprotic polar/non-polar solvent such as DMF, THF or CH₂Cl₂ attemperatures range between 0°-100° C. for time range of 1-60 hrs, orunder microwave irradiation in the presence of DMAP and a Lewis acidsuch as Sc(OTf)₃ or Bi(OTf)₃ in solvents such as DMF, CH₂Cl₂ attemperatures range between 60°-120° C. for time range of 1-120 min;

Compounds (IIIu) can be prepared from compounds Act-(O)C—NH—Y—OH (IIIu)by nitrating reactions with tetraalkylammonium nitrate as alreadydescribed. Compounds (IIIu) can be prepared from commercially availableAct-CO-Hal (IIIw) and compounds W₃NH—Y—OH (IIIt) with the proviso thatin (IIIt) W₃ has only the meaning of —H.

30. The compounds of general formula (I) wherein:

s and s′ are equal to 1;s″, m, m′, m″, are 0Y and Y′ are equal or different and are as above defined;A is a radical of formula (IIs) wherein R₃ is —C(O)—R_(3x) and it bindsthe group —Y—ONO₂ or the group —Y′—ONO₂; R₁ is —C(O)—R_(1x) and it bindsthe group —Y—ONO₂ or the group —Y′—ONO₂;R_(s) is selected in group a″), can be prepared as follows:

30a) Y and Y′ are equal

by reacting compounds of formula A described in 25a) with a compound offormula (IIIe)

Act-(O)C—Y—ONO₂  (IIIe)

wherein Y and Act are as above defined; A is a compound of formula (IIs)wherein R₁ is —H, R₃ is —OH and R_(s) is selected in group a″), using aratio A/(IIIe) 1:2 and applying the same procedure described in 1b′).

30a′) Y and Y′ are equal or different

by reacting compounds of formula (I) prepared in 25. with a compound offormula (IIIe)

A-Y—ONO₂+Act-(O)C—Y′—ONO₂  (IIIe)

wherein Y, Y′ and Act are as above defined; A is a compound of formula(IIs) wherein R₁ is —C(O)—R_(1x) and binds the group —Y—ONO₂, R₃ is —OHand R_(s) is selected in group a″), applying the same proceduredescribed in 1b′).

30a″) Y and Y′ are equal or different

by reacting compounds of formula (I) prepared in 27. with a compound offormula (IIIe)

A-Y—ONO₂+Act-(O)C—Y′—ONO₂  (IIIe)

wherein Y, Y′ and Act are as above defined; A is selected from (IIs)wherein R₁ is —H, and R₃ is —C(O)—R_(3x) and R_(s) is selected in groupa″), applying the same procedure described in 1b′).

31. The compounds of general formula (I) wherein:

s and s′ are equal to 1;s″, m, m′, m″, are 0Y and Y′ are equal or different and are as above defined;A is a radical of formula (IIs) wherein R₃ is —C(O)O—R_(3x)— and itbinds the group —Y—ONO₂ or the group —Y′—ONO₂; R₁ is —C(O)—R_(1x) and itbinds the group —Y—ONO₂ or the group —Y′—ONO₂, R_(s) is selected ingroup a″), can be prepared as follows:

31a) by reacting compounds of formula (I) obtained in procedure 25. witha compound of formula (IIIf)

A-Y—ONO₂+Act-(O)C—O—Y′—ONO₂  (IIIf)

wherein Y, Y′ and Act are as above defined; A is a radical of formula(IIs) wherein R₁ is —C(O)—R_(1x) and it binds the group —Y—ONO₂, R₃ is—OH and R_(s) is selected in group a″), applying the same proceduredescribed in 28b).

31a′) alternatively by reacting compounds of formula (I) prepared asdescribed in 28. with a compound of formula (IIIe)

A-Y—ONO₂+Act-(O)C—Y′—ONO₂  (IIIe)

wherein Y, Y′ and Act are as above defined; A is the radical of formula(IIs) wherein R₁ is —H, R₃ is —C(O)O—R_(3x) and R₃ binds the group—Y—ONO₂, R_(s) is selected in group a″), applying the same proceduredescribed in 25a).

32. The compounds of general formula (I) wherein:

s and s′ are equal to 1;s″, m, m′, m″, are 0Y and Y′ are equal or different and are as above defined;A is a radical of formula (IIs) wherein R₃ is —C(O)—NH—R_(3x) and itbinds the group —Y—ONO₂; R₁ is —C(O)—R_(1x) and it binds the group—Y′—ONO₂, R₁ is selected in group a″), can be prepared as follows:

32a) by reacting compounds of formula (I) obtained in procedure 29. witha compound of formula (IIIe)

wherein Y, Y′ and Act are as above defined; A is a radical of formula(IIs) wherein R₁ is —H, R₃ is —C(O)—NH—R_(3x) and it binds the group—Y—ONO₂, R_(s) is selected in group a″),applying the same procedure described in 25a).

33. The compounds of general formula (I) wherein:

s and s′ are equal to 1;s″, m, m′, m″, are 0Y and Y′ are equal or different and are as above defined;A is a radical of formula (IIs) wherein R₃ is —OC(O)—R_(3x) and it bindsthe group —Y′—ONO₂; R₁ is —C(O)O—R_(1x) and it binds the group —Y—ONO₂,R_(s) is selected in group a″), can be prepared as follows:

33a) by reacting compounds of formula (I) obtained in procedure 26. witha compound of formula (IIIe)

wherein Y, Y′ and Act are as above defined; A is a radical of formula(IIs) wherein R₁ is —C(O)O—R_(1x) and it binds the group —Y—ONO₂, R₃ is—OH and R_(s) is selected in group a″),applying the same procedure described in 27b).

34. The compounds of general formula (I) wherein:

s and s′ are equal to 1;s″, m, m′, m″, are 0Y and Y′ are equal or different and are as above defined;A is a radical of formula (IIs) wherein R₃ is —C(O)O—R_(3x) and it bindsthe group —Y—ONO₂ or the group —Y′—ONO₂; R₁ is —C(O)O—R_(1x) and itbinds the group —Y—ONO₂ or the group —Y′—ONO₂, R_(s) is selected ingroup a″), can be prepared as follows:

34a) Y and Y′ are equal;

by reacting compounds of formula A described in 25a) with a compound offormula (IIIf)

A+Act-(O)C—O—Y′—ONO₂  (IIIf)

wherein Y, Y′ and Act are as above defined; A is a compound of formula(IIs) wherein R₁ is —H, R₃ is —OH and R_(s) is selected in group a″),using a ratio A/(IIIf) 1:2 and applying the same procedure described in3b).

34a′) Y and Y′ are equal or different

by reacting compounds of formula (I) prepared in 26. with a compound offormula (IIIf)

wherein Y, Y′ and Act are as above defined; A is a radical of formula(IIs) wherein R₁ is —C(O)O—R_(1x) and it binds the group —Y—ONO₂ and R₃is —OH, R_(s) is selected in group a″); applying the same proceduredescribed in 3b).

34a″) Y and Y′ are equal or different

by reacting compounds of formula (I) prepared in 28. with a compound offormula (IIIf)

wherein Y, Y′ and Act are as above defined; A is a radical of formula(IIs) wherein R₁ is —H, R₃ is —C(O)O—R_(3x) and R₃ binds the group—Y—ONO₂, R_(s) is selected in group a″), applying the same proceduredescribed in 3b).

35. The compounds of general formula (I) wherein:

s and s′ are equal to 1;s″, m, m′, m″, are 0Y and Y′ are equal or different and are as above defined;A is a radical of formula (IIs) wherein R₃ is —C(O)—NH—R_(3x) and itbinds the group —Y′—ONO₂; R₁ is —C(O)O—R_(1x) and it binds the group—Y—ONO₂, R_(s) is selected in group a″),can be prepared as follows:

35a) by reacting compounds of formula (I) obtained in procedure 26. witha compound of formula (IIIu)

wherein Y, Y′ and Act are as above defined; A is a radical of formula(IIs) wherein R₁ is —C(O)O—R_(1x) and it binds the group —Y—ONO₂, R₃ is—OH and R_(s) is selected in group a″),using the same procedure described in 29b).

35a′) alternatively by reacting compound of formula (I) prepared in 29.with a compound of formula (IIIf)

wherein Y, Y′ and Act are as above defined; A is a radical of formula(IIs) wherein R₁ is —H, R₃ is —C(O)—NH—R_(3x) and it binds the group—Y—ONO₂, R_(s) is selected in group a″),applying the same procedure described in 3b).

36. The compounds of general formula (I) wherein:

s is equal to 1;

s′ can be 0 or 1; with the proviso that s′ is 1 when A is the radical(IIs) and (IIs) is as defined in iii) below reported,

s″, m, m′, m″, are 0Y and Y′ when presents are equal and are as above defined;A is selected among:i) (IIa) wherein R₁ is —H, R₂ is —COOH and R_(a) is selected fromR_(bx)—C(O)—S—CH₂—, or R_(x)O—CH₂—, R_(x)O—CH(CH₃)—,(R_(x)O)-p-C₆H₄—CH₂—,4-(R_(x)O)-3,5-diiodobenzyl-4-(R_(x)O)-3-nitrobenzyl- whereinR_(x)—C(O)— and R_(a) binds a group —Y—ONO₂;ii) (IIc) wherein R₁ is —H, R₂ is —COOH and R_(x) is selected fromR_(bx)—C(O)—S—CH₂—, or R_(x)O—CH₂—, R_(x)O—CH(CH₃)—,(R_(x)O)-p-C₆H₄—CH₂—,4-(R_(x)O)-3,5-diiodobenzyl-4-(R_(x)O)-3-nitrobenzyl- whereinR_(x)—C(O)— and R_(c) binds a group —Y—ONO₂;iii) (IIs) (s′ is 1) wherein R₁ is —H, R₃ is —OC(O) and R_(s) isselected from R_(bx)—C(O)—S—CH₂—, or R_(x)O—CH₂—, R_(x)O—CH(CH₃)—,(R_(x)O)-p-C₆H₄—CH₂—,4-(R_(x)O)-3,5-diiodobenzyl-4-(R_(x)O)-3-nitrobenzyl- wherein R_(x) isR_(xx)—C(O)—; both R₃ and R_(s) bind a group —Y—ONO₂ or a group—Y′—ONO₂;vi) (IIs) (s′ is 0) wherein R₁ is —H, R₃ is —OC(O) and R₃ binds a group—Y—ONO₂; R_(s) is selected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂,R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—, wherein R_(g) is —OH;v) (IIu) wherein R₁ is —H, R₂ is —COOH, a is 1: b is 0 or 1; and R_(x)is R_(xx)—C(O)— and R_(x) binds a group —Y—ONO₂;can be prepared as follows:

36a) by reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″,Y, Y′, Y″ are as above defined in 36, A is a radical of formula (IIa),(IIc), (IIs) or (IIu) wherein; R₂, R₃, a, b, R_(a), R_(c), R_(s), R_(g)and R_(x) are as defined in 36; R₁ is —C(O)OC(CH₃)₃ with anhydrous oraqueous organic or inorganic acid to hydrolyze the —BOC protectivegroups following procedure well known in the literature.

36b) by reacting a compound of formula A with a compound of formula(IIIa)

A+Act(O)C—Y—ONO₂  (IIIe)

wherein Act and Y are as above defined and A has the following meanings:i′) a radical of formula (IIa) wherein R₁ is —C(O)OC(CH₃)₃, R₂ is —COOHand R_(a) is selected from HS—CH₂—, or R_(x)O—CH₂—, R_(x)O—CH(CH₃)—,(R_(x)O)-p-C₆H₄—CH₂—,4-(R_(x)O)-3,5-diiodobenzyl-4-(R_(x)O)-3-nitrobenzyl- wherein R_(x)—H;ii′) a radical of formula (IIc) wherein R₁ is —C(O)OC(CH₃)₃, R₂ is —COOHand R_(c) is selected from HS—CH₂—, or R_(x)O—CH₂—, R_(x)O—CH(CH₃)—,(R_(x)O)-p-C₆H₄—CH₂—,4-(R_(x)O)-3,5-diiodobenzyl-4-(R_(x)O)-3-nitrobenzyl- wherein R_(x)—H;iii′) a radical of formula (IIs) wherein R₁ is —C(O)OC(CH₃)₃, R₃ is —OHand R_(s) is selected from HS—CH₂—, or R_(x)O—CH₂—, R_(x)O—CH(CH₃)—,(R_(x)O)-p-C₆H₄—CH₂—,4-(R_(x)O)-3,5-diiodobenzyl-4-(R_(x)O)-3-nitrobenzyl- wherein R_(x)—H;iv′) a radical of formula (IIs) wherein R₁ is —C(O)OC(CH₃)₃, R₃ is —OH;R_(s) is R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—,R_(g)C(O)(CH₂)₄—, wherein R_(g) is —OH;v′) a radical of formula (IIu) wherein R₁ is —C(O)OC(CH₃)₃, R₂ is —COOH,a is 1; b is 0 or 1 and R_(x) is —H;following the same procedure described in 1b′) using a ratio A/(IIIe)1:1 or 1:2 for s′ equal to 1.

37. The compounds of general formula (I) wherein:

s is equal to 1;s′ can be 0 or 1; with the proviso that s′ is 1 when A is the radical(IIs) and (IIs) is as defined in iii),S″, m, m′, m″, are 0Y and Y′, when present are equal and are as above defined;A is selected among:i) (IIa) wherein R₁ is —H, R₂ is —COOH and R_(a) is selected fromR_(bx)—OC(O)—S—CH₂—, or R_(x)O—CH₂—, R_(x)O—CH(CH₃)—,(R_(x)O)-p-C₆H₄—CH₂—,4-(R_(x)O)-3,5-diiodobenzyl-4-(R_(x)O)-3-nitrobenzyl- wherein R_(x) isR_(xx)—OC(O)— and R_(a) binds a group —Y—ONO₂;ii) (IIc) wherein R₁ is —H, R₂ is —COOH and R_(b) is selected fromR_(bx)—OC(O)—S—CH₂—, or R_(x)O—CH₂—, R_(x)O—CH(CH₃)—,(R_(x)O)-p-C₆H₄—CH₂—,4-(R_(x)O)-3,5-diiodobenzyl-4-(R_(x)O)-3-nitrobenzyl- wherein R_(x) isR_(xx)—CC(O)— and R_(b) binds a group —Y—ONO₂;iii) (IIs) (s′ is 1) wherein R₁ is —H, R₃ is —C(O)O—R_(3x) and R_(s) isselected from R_(bx)—OC(O)—S—CH₂—, or R_(x)O—CH₂—, R_(x)O—CH(CH₃)—,(R_(x)O)-p-C₆H₄—CH₂—,4-(R_(x)O)-3,5-diiodobenzyl-4-(R_(x)O)-3-nitrobenzyl- wherein R_(x) isR_(xx)—OC(O)— both R₃ and R_(s) bind a group —Y—ONO₂ or a group—Y′—ONO₂;vi) (IIs) (s′ is 0) wherein R₁ is —H, R₃ is —OC(O)O—R_(3x) and R₃ bindsa group —Y—ONO₂; R_(s) is selected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂,R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—, wherein R_(g) is —OH;v) (IIu) wherein R₁ is —H, R₂ is —COOH, a is 1; b is 0 or 1; and R_(x)is R_(xx)—OC(O)— and R_(x) binds a group —Y—ONO₂;can be prepared as follows:

37a) by reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″,Y, Y′, Y″ are as above defined in 37, A is a radical of formula (IIa),(IIc), (IIs) or (IIu) wherein; R₂, R₃, a, b, R_(a), R_(c), R_(s), R_(g)and R_(x) are as defined in 37; R₁ is —C(O)OC(CH₃)₃ with anhydrous oraqueous organic or inorganic acid to hydrolyze the —BOC protectivegroups following procedure well known in the literature.

37b) by reacting a compound of formula A with a compound of formula(IIIf)

A+Act(O)C—O—Y—ONO₂  (IIIf)

wherein Act and Y are as above defined and A has the same meaningsdescribed in 36b);following the same procedure described in 3b) using a ratio A/(IIIf) 1:1or 1:2 for s′ equal to 1.

38. The compounds of general formula (I) wherein:

s is equal to 1;s′ can be 0 or 1; with the proviso that s′ is 1 when A is the radical(IIs) and (IIs) is as defined in iii),s″, m, m′, m″, are 0Y and Y′, when presents, are equal and are as above defined;A is selected among:i) (IIa) wherein R₁ is —H, R₂ is —COOH and R_(a) is selected fromR_(bx)—NH(O)C—S—CH₂—, or R_(x)O—CH₂—, R_(x)O—CH(CH₃)—,(R_(x)O)-p-C₆H₄—CH₂—,4-(R_(x)O)-3,5-diiodobenzyl-4-(R_(x)O)-3-nitrobenzyl- wherein R_(x) isR_(xx)NH—C(O)— and R_(a) binds a group —Y—ONO₂;ii) (IIc) wherein R₁ is —H, R₂ is —COOH and R_(c) is selected fromR_(bx)—NH(O)C—S—CH₂—, or R_(x)O—CH₂—, R_(x)O—CH(CH₃)—,(R_(x)O)-p-C₆H₄—CH₂—,4-(R_(x)O)-3,5-diiodobenzyl-4-(R_(x)O)-3-nitrobenzyl- wherein R_(x) isR_(xx)NH—C(O)— and R_(c) binds a group —Y—ONO₂;iii) (IIs) (s′ is 1) wherein R₁ is —H, R₃ is —C(O)—NH—R_(3x) and R_(s)is selected from R_(bx)—NH(O)C—S—CH₂—, or R_(x)O—CH₂—, R_(x)O—CH(CH₃)—,(R_(x)O)-p-C₆H₄—CH₂—,4-(R_(x)O)-3,5-diiodobenzyl-4-(R_(x)O)-3-nitrobenzyl- wherein R_(x) isR_(xx)NH—C(O)— both R₃ and R_(s) bind a group —Y—ONO₂ or a group—Y′—ONO₂;vi) (IIs) (s′ is 0) wherein R₁ is —H, R₃ is —C(O)—NH—R_(3x) and R₃ bindsa group —Y—ONO₂; R_(s) is selected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂,R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—, wherein R_(g) is —OH;v) (IIu) wherein R₁ is —H, R₂ is —COOH, a is 1; b is 0 or 1; and R_(x)is R_(xx)—NHC(O)— and R_(x) binds a group —Y—ONO₂;can be prepared as follows:

38a) by reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″,Y, Y′, Y″ are as above defined in 38, A is a radical of formula (IIa),(IIc), (IIs) or (IIu) wherein; R₂, R₃, a, b, R_(a), R_(c), R_(s), R_(g)and R_(x) are as defined in 38; R₁ is —C(O)OC(CH₃)₃ with anhydrous oraqueous organic or inorganic acid to hydrolyze the —BOC protectivegroups following procedure well known in the literature.

38b) by reacting a compound of formula A with a compound of formula(IIIu)

A+Act(O)C—NH—Y—ONO₂  (IIIu)

wherein Act and Y are as above defined and A has the same meaningsdescribed in 36b);following the same procedure described in 29. using a ratio A/(IIIu) 1:1or 1:2 for s′ equal to 1.

39. The compounds of general formula (I) wherein:

s and s′ are equal to 1;s″, m, m′, m″, are 0Y and Y′ are equal or different and are as above defined;A is selected among:i) (IIa) wherein R₁ is —H, R₂ is —C(O)OR_(2x) and R₂ binds a group—Y′—ONO₂; and R_(a) is selected from R_(bx)—C(O)—S—CH₂—, or R_(x)O—CH₂—,R_(x)O—CH(CH₃)—, (R_(x)O)-p-C₆H₄—CH₂—,4-(R_(x)O)-3,5-diiodobenzyl-4-(R_(x)O)-3-nitrobenzyl- wherein R_(x) isR_(xx)—C(O)— and R_(a) binds a group —Y—ONO₂;ii) (IIc) wherein R₁ is —H, R₂ is —C(O)OR_(2x) and R₂ binds a group—Y′—ONO₂; R_(c) is selected from R_(bx)—C(O)—S—CH₂—, or R_(x)O—CH₂—,R_(x)O—CH(CH₃)—, (R_(x)O)-p-C₆H₄—CH₂—,4-(R_(x)O)-3,5-diiodobenzyl-4-(R_(x)O)-3-nitrobenzyl- wherein R_(x) isR_(xx)—C(O)— and R_(c) binds a group —Y—ONO₂;iii) (IIs) wherein R₁ is —H, R₃ is —OC(O)R_(3x) and R₃ binds a group—Y—ONO₂; R_(s) is selected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂,R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—, wherein R_(g) is R_(gx)—O—, andR_(s) binds a group —Y′—ONO₂;v) (IIu) wherein R₁ is —H, R₂ is —C(O)O—R_(2x), R₂ binds a group—Y′—ONO₂; a is 1; b is 0 or 1; and R_(x) is R_(xx)—C(O)— and R_(x) bindsa group —Y—ONO₂;can be prepared as follows:

39a) by reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″,Y, Y′, Y″ are as above defined in 39, A is a radical of formula (IIa),(IIc), (IIs) or (IIu) wherein; R₂, R₃, a, b, R_(a), R_(c), R_(s), R_(g)and R_(x) are as defined in 39; R₁ is —C(O)OC(CH₃)₃ with anhydrous oraqueous organic or inorganic acid to hydrolyze the —BOC protectivegroups following procedure well known in the literature.

39b) by reacting a compound of formula (I) obtained in 36b) with acompound of formula (IIIi)

wherein Y and Y′ are as above defined and in formula (I) A is a radicalof formula (IIa), (IIc), (IIs) or (IIu) wherein R₁ is —C(O)OC(CH₃)₃, R₂is —COOH, R₃, R_(a), R_(c) R_(x) a and b are as above defined in 39;R_(s) is R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—,R_(g)C(O)(CH₂)₄—, wherein R_(g) is —OH;following the same procedure described in 8b).

40. The compounds of general formula (I) wherein:

s and s′ are equal to 1;s″, m, m′, m″, are 0Y and Y′ are equal or different and are as above defined;A is selected among:i) (IIa) wherein R₁ is —H, R₂ is —C(O)OR_(2x) and R₂ binds a group—Y′—ONO₂; and R_(a) is selected from R_(bx)—OC(O)—S—CH₂—, orR_(x)O—CH₂—, R_(x)O—CH(CH₃)—, (R_(x)O)-p-C₆H₄—CH₂—,4-(R_(x)O)-3,5-diiodobenzyl-4-(R_(x)O)-3-nitrobenzyl- wherein R_(x) isR_(xx)—OC(O)— and R_(a) binds a group —Y—ONO₂;ii) (IIc) wherein R₁ is —H, R₂ is —C(O)OR_(2x) and R₂ binds a group—Y′—ONO₂; R_(c) is selected from R_(bx)—OC(O)—S—CH₂—, or R_(x)O—CH₂—,R_(x)O—CH(CH₃)—, (R_(x)O)-p-C₆H₄—CH₂—,4-(R_(x)O)-3,5-diiodobenzyl-4-(R_(x)O)-3-nitrobenzyl- wherein R_(x) isR_(xx)—OC(O)— and R_(c) binds a group —Y—ONO₂;iii) (IIs) wherein R₁ is —H, R₃ is —OC(O)O—R_(3x) and R₃ binds a group—Y—ONO₂; R_(s) is selected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂.R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—, wherein R_(g) is R_(gx)—O—, andR_(s) binds a group —Y′—ONO₂;v) (IIu) wherein R₁ is —H, R₂ is —C(O)O—R_(2x), R₂ binds a group—Y′—ONO₂; a is 1; b is 0 or 1 and R_(x) is R_(xx)—OC(O)— and R_(x) bindsa group —Y—ONO₂;can be prepared as follows:

40a) by reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″,Y, Y′, Y″ are as above defined in 40, A is a radical of formula (IIa),(IIc), (IIs) or (IIu) wherein; R₂, R₃, a, b, R_(a), R_(c), R_(s), R_(g)and R_(x) are as defined in 40; R₁ is —C(O)OC(CH₃)₃ with anhydrous oraqueous organic or inorganic acid to hydrolyze the —BOC protectivegroups following procedure well known in the literature.

40b) by reacting a compound of formula (I) obtained in 37b) with acompound of formula (IIIi)

wherein Y and Y′ are as above defined and in formula (I) A is a radicalof formula (IIa), (IIc), (IIs) or (IIu) wherein R₁ is —C(O)OC(CH₃)₃, R₂is —COOH, R₃, R_(a), R_(c) R_(x) a and b are as above defined in 40,R_(s) is R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—,R_(g)C(O)(CH₂)₄—, wherein R_(g) is —OH;following the same procedure described in 8b).

41. The compounds of general formula (I) wherein:

s and s′ are equal to 1;s″, m, m′, m″, are 0Y and Y′ are equal or different and are as above defined;A is selected among:i) (IIa) wherein R₁ is —H, R₂ is —C(O)OR_(2x) and R₂ binds a group—Y′—ONO₂; and R_(a) is selected from R_(bx)—NH(O)C—S—CH₂—, orR_(x)O—CH₂—, R_(x)O—CH(CH₃)—, (R_(x)O)-p-C₆H₄—CH₂—,4-(R_(x)O)-3,5-diiodobenzyl-4-(R_(x)O)-3-nitrobenzyl- wherein R_(x) isR_(xx)NH—C(O)— and R_(a) binds a group —Y—ONO₂;ii) (IIc) wherein R₁ is —H, R₂ is —C(O)OR_(2x) and R₂ binds a group—Y′—ONO₂; R_(c) is selected from R_(bx)—NH(O)C—S—CH₂—, or R_(x)O—CH₂—,R_(x)O—CH(CH₃)—, (R_(x)O)-p-C₆H₄—CH₂—,4-(R_(x)O)-3,5-diiodobenzyl-4-(R_(x)O)-3-nitrobenzyl- wherein R_(x) isR_(xx)NH—C(O)— and R_(c) binds a group —Y—ONO₂;iii) (IIs) wherein R₁ is —H, R₃ is —OC(O)—NH—R_(3x) and R₃ binds a group—Y—ONO₂; R_(s) is selected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂,R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—, wherein R_(g) is R_(gx)—O—, andR_(s) binds a group —Y′—ONO₂;v) (IIu) wherein R₁ is —H, R₂ is —C(O)O—R_(2x), R₂ binds a group—Y′—ONO₂; a is 1; b is 0 or 1 and R_(x) is R_(xx)—NHC(O)— and R_(x)binds a group —Y—ONO₂;can be prepared as follows:

41a) by reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″,Y, Y′, Y″ are as above defined in 41, A is a radical of formula (IIa),(IIc), (IIs) or (IIu) wherein; R₂, R₃, a, b, R_(a), R_(c), R_(s), R_(g)and R_(x) are as defined in 41; R₁ is —C(O)OC(CH₃)₃ with anhydrous oraqueous organic or inorganic acid to hydrolyze the —BOC protectivegroups following procedure well known in the literature.

41b) by reacting a compound of formula (I) obtained in 38b) with acompound of formula (IIIi)

wherein Y and Y′ are as above defined and in formula (I) A is a radicalof formula (IIa), (IIc), (IIs) or (IIu) wherein R₁ is —C(O)OC(CH₃)₃, R₂is —COOH, R₃, R_(a), R_(c) R_(x) a and b are as above defined in 41,R_(s) is R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—,R_(g)C(O)(CH₂)₄—, wherein R_(g) is —OH;following the same procedure described in 8b).

42. The compounds of general formula (I) wherein:

s and s′ are equal to 1;s″, m, m′, m″, are 0Y and Y′ are equal or different and are as above defined;A is selected among:i) (IIa) wherein R₁ is —H, R₂ is —C(O)NHR_(2xx) or —C(O)N(CH₃)R_(2xx)and R₂ binds a group —Y′—ONO₂; and R_(a) is selected fromR_(bx)—C(O)—S—CH₂—, or R_(x)O—CH₂—, R_(x)O—CH(CH₃)—,(R_(x)O)-p-C₆H₄—CH₂—,4-(R_(x)O)-3,5-diiodobenzyl-4-(R_(x)O)-3-nitrobenzyl- wherein R_(x) isR_(xx)—C(O)— and R_(a) binds a group —Y—ONO₂;ii) (IIc) wherein R₁ is —H, R₂ is —C(O)NHR_(2xx) or —C(O)N(CH₃)R_(2xx)and R₂ binds a group —Y′—ONO₂; R_(x) is selected from R_(bx)—C(O)—S—CH₂—or R_(x)O—CH₂—, R_(x)O—CH(CH₃)—, (R_(x)O)-p-C₆H₄—CH₂—,4-(R_(x)O)-3,5-diiodobenzyl-4-(R_(x)O)-3-nitrobenzyl- wherein R_(x) isR_(xx)—C(O)— and R_(c) binds a group —Y—ONO₂;iii) (IIs) wherein R₁ is —H, R₃ is —OC(O)R_(3x) and R₃ binds a group—Y—ONO₂; R_(s) is selected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂,R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—, wherein R_(g) is R_(gxx)—NH— orR_(gxx)—N(CH₃)— and R_(s) binds a group —Y′—ONO₂;v) (IIu) wherein R₁ is —H, R₂ is —C(O)NHR_(2xx) or —C(O)N(CH₃)R_(2xx)and R₂ binds a group —Y′—ONO₂; a is 1; b is 0 or 1 and R_(x) isR_(xx)—C(O)— and R_(x) binds a group —Y—ONO₂;can be prepared as follows:

42a) by reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″,Y, Y′, Y″ are as above defined in 42, A is a radical of formula (IIa),(IIc), (IIs) or (IIu) wherein; R₂, R₃, a, b, R_(a), R_(c), R_(s), R_(g)and R_(x) are as defined in 42; R₁ is —C(O)OC(CH₃)₃ with anhydrous oraqueous organic or inorganic acid to hydrolyze the —BOC protectivegroups following procedure well known in the literature.

42b) by reacting a compound of formula (I) obtained in 36b) with acompound of formula (IIIo)

wherein Y and Y′ are as above defined, W₃ is as above defined and informula (I) A is a radical of formula (IIa), (IIc), (IIs) or (IIu)wherein R₁ is —C(O)OC(CH₃)₃, R₂ is —COOH, R₃, R_(a), R_(c) R_(x) a and bare as above defined in 42, R_(s) is R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂,R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—, wherein R_(g) is —OH;following the same procedure described in 7b).

43. The compounds of general formula (I) wherein:

s and s′ are equal to 1;s″, m, m′, m″, are 0Y and Y′ are equal or different and are as above defined;A is selected among:i) (IIa) wherein R₁ is —H, R₂ is —C(O)NHR_(2xx) or —C(O)N(CH₃)R_(2xx)and R₂ binds a group —Y′—ONO₂; and R_(a) is selected fromR_(bx)—OC(O)—S—CH₂—, or R_(x)O—CH₂—, R_(x)O—CH(CH₃)—,(R_(x)O)-p-C₆H₄—CH₂—,4-(R_(x)O)-3,5-diiodobenzyl-4-(R_(x)O)-3-nitrobenzyl- wherein R_(x) isR_(xx)—OC(O)— and R_(a) binds a group —Y—ONO₂;ii) (IIc) wherein R₁ is —H, R₂ is —C(O)NHR_(2xx) or —C(O)N(CH₃)R_(2xx)and R₂ binds a group —Y′—ONO₂; R_(c) is selected fromR_(bx)—OC(O)—S—CH₂—, or R_(x)O—CH₂—, R_(x)O—CH(CH₃)—,(R_(x)O)-p-C₆H₄—CH₂—,4-(R_(x)O)-3,5-diiodobenzyl-4-(R_(x)O)-3-nitrobenzyl- wherein R_(x) isR_(xx)—OC(O)— and R_(c) binds a group —Y—ONO₂;iii) (IIs) wherein R₁ is —H, R₃ is —C(O)O—R_(3x) and R₃ binds a group—Y—ONO₂; R_(s) is selected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂,R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—, wherein R_(g) is R_(gxx)—NH— orR_(2xx)—N(CH₃)— and R_(s) binds a group —Y′—ONO₂;v) (IIu) wherein R₁ is —H, R₂ is —C(O)NHR_(2xx) or —C(O)NHR_(2xx) and R₂binds a group —Y′—ONO₂; a is 1; b is 0 or 1 and R_(x) is R_(xx)—OC(O)—and R_(x) binds a group —Y—ONO₂;can be prepared as follows:

43a) by reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″,Y, Y′, Y″ are as above defined in 43, A is a radical of formula (IIa),(IIc), (IIs) or (IIu) wherein; R₂, R₃, a, b, R_(a), R_(c), R_(s), R_(g)and R_(x) are as defined in 43; R₁ is —C(O)OC(CH₃)₃ with anhydrous oraqueous organic or inorganic acid to hydrolyze the —BOC protectivegroups following procedure well known in the literature.

43b) by reacting a compound of formula (I) obtained in 37b) with acompound of formula (IIIo)

wherein Y and Y′ are as above defined, W₃ is as above defined and informula (I) A is a radical of formula (IIa), (IIc), (IIs) or (IIu)wherein R₁ is —C(O)OC(CH₃)₃, R₂ is —COOH, R₃, R_(a), R_(c) R_(x) a and bare as above defined in 43, R_(s) is R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂.R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—, wherein R_(g) is —OH;following the same procedure described in 7b).

44. The compounds of general formula (I) wherein:

s and s′ are equal to 1;s″, m, m′, m″, are 0Y and Y′ are equal or different and are as above defined;A is selected among:i) (IIa) wherein R₁ is —H, R₂ is —C(O)NHR_(2xx) or —C(O)N(CH₃)R_(2xx)and R₂ binds a group —Y′—ONO₂; and R_(a) is selected fromR_(bx)—NH(O)C—S—CH₂—, or R_(x)O—CH₂—, R_(x)O—CH(CH₃)—,(R_(x)O)-p-C₆H₄—CH₂—, 4-(R_(x)O)-3,5-R_(xx)NH—C(O)— and R_(a) binds agroup —Y—ONO₂;ii) (IIc) wherein R₁ is —H, R₂ is —C(O)NHR_(2xx) or —C(O)N(CH₃)R_(2xx)and R₂ binds a group —Y′—ONO₂; R_(c) is selected fromR_(bx)—NH(O)C—S—CH₂—, or R_(x)O—CH₂—, R_(x)O—CH(CH₃)—,(R_(x)O)-p-C₆H₄—CH₂—,4-(R_(x)O)-3,5-diiodobenzyl-4-(R_(x)O)-3-nitrobenzyl- wherein R_(x) isR_(xx)NH—C(O)— and R_(c) binds a group —Y—ONO₂;iii) (IIs) wherein R₁ is —H, R₃ is —C(O)—NH—R_(3x) and R₃ binds a group—Y—ONO₂; R_(s) is selected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂.R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—, wherein R_(g) is R_(gxx)—NH— orR_(2xx)—N(CH₃)— and R_(s) binds a group —Y′—ONO₂;v) (IIu) wherein R₁ is —H, R₂ is —C(O)NHR_(2xx) or —C(O)N(CH₃)R_(2xx) R₂binds a group —Y′—ONO₂; a is 1; b is 0 or 1; and R_(x) is R_(xx)—NHC(O)—and R_(x) binds a group —Y—ONO₂;can be prepared as follows:

44a) by reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″,Y, Y′, Y″ are as above defined in 44, A is a radical of formula (IIa),(IIc), (IIs) or (IIu) wherein; R₂, R₃, a, b, R_(a), R_(c), R_(s), R_(g)and R_(x) are as defined in 44; R₁ is —C(O)OC(CH₃)₃ with anhydrous oraqueous organic or inorganic acid to hydrolyze the —BOC protectivegroups following procedure well known in the literature.

44b) by reacting a compound of formula (I) obtained in 38b) with acompound of formula (IIIo)

wherein Y and Y′ are as above defined, W₃ is as above defined and informula (I) A is a radical of formula (IIa), (IIc), (IIs) or (IIu)wherein R₁ is —C(O)OC(CH₃)₃, R₂ is —COOH, R₃, R_(a), R_(c) R_(x) a and bare as above defined in 44, R_(s) is R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂,R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—, wherein R_(g) is —OH;following the same procedure described in 7b).

45. The compounds of general formula (I) wherein:

s is equal to 1;s′, s″, m, m′, m″, are 0Y is as above defined;A is selected among:i) (IIa) wherein R₁ is —H, R₂ is —C(O)OR_(2x) and R₂ binds a group—Y—ONO₂; and R_(a) is selected from HS—CH₂—, or R_(x)O—CH₂—,R_(x)O—CH(CH₃)—, (R_(x)O)-p-C₆H₄—CH₂—,4-(R_(x)O)-3,5-diiodobenzyl-4-(R_(x)O)-3-nitrobenzyl- wherein R_(x)—H;ii) (IIc) wherein R₁ is —H, R₂ is —C(O)OR_(2x) and R₂ binds a group—Y—ONO₂; and R_(a) is selected from HS—CH₂—, or R_(x)O—CH₂—,R_(x)O—CH(CH₃)—, (R_(x)O)-p-C₆H₄—CH₂—,4-(R_(x)O)-3,5-diiodobenzyl-4-(R_(x)O)-3-nitrobenzyl- wherein R_(x)—H;iii) (IIs) wherein R₁ is —H, R₃ is —H; R_(s) is selected fromR_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—,wherein R_(g) is R_(gx)—O—, and R_(s) binds a group —Y—ONO₂;v) (IIu) wherein R₁ is —H, R₂ is —C(O)OR_(2x), R₂ binds a group —Y—ONO₂;a is 1; b is 0 or 1 and R_(x) is —H;can be prepared as follows:

45a) by reacting a compound of formula (VIIa)

A_(3a)-Y—ONO₂  (VIIa)

wherein Y is as above defined and A_(3a) is a radical of formula (IIa),(IIc), (IIs) or (IIu) wherein R₂, a, b and R_(s) are as defined in 45;R₁ is —C(O)OC(CH₃)₃;in formula (IIs) R₃ is equal to R_(3a) wherein R_(3a) is —OTrt, whereinTrt is the trityl protecting group; in formula (IIa) and (IIc) R_(a) andR_(c) have the meanings: Trt-S—CH₂—, or R_(xa)O—CH₂—, R_(xa)O—CH(CH₃)—,(R_(xa)O)-p-C₆H₄—CH₂—,4-(R_(xa)O)-3,5-diiodobenzyl-4-(R_(xa)O)-3-nitrobenzyl- wherein R_(xa)is -Trt, the trityl protecting group or the dimethyltertbutylsilylgroup;in formula (IIu) R_(x) is equal to R_(xa), wherein R_(xa) is as abovedefined;with anhydrous or aqueous organic or inorganic acid to hydrolyze the—BOC and the other protective groups following procedure well known inthe literature.

45b) by reacting a compound of formula A₃ with a compound of formula(IIIi)

A₃+HO—Y—ONO₂  (IIIi)

wherein Y is as above defined and A₃ is a radical of formula (IIa),(IIc), (IIs) or (IIu) wherein R₁ is —C(O)OC(CH₃)₃, R₂ is —COOH, a is asabove defined in 45, R₃ is equal to R_(3a) and is —OTrt, R_(a) and R_(c)are TrtS—CH₂—, or R_(xa)O—CH₂—, R_(xa)O—CH(CH₃)—, (R_(xa)O)-p-C₆H₄—CH₂—,4-(R_(xa)O)-3,5-diiodobenzyl-4-(R_(xa)O)-3-nitrobenzyl- wherein R_(xa)is as above defined; R_(x) of formula (IIu) is equal to R_(xa) and is asabove defined; R_(s) is R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂,R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—, wherein R_(g) is —OH;following the same procedure described in 8b).

Compounds A₃ are commercially available or can be prepared fromcommercially available compounds by simple de-protection/protectionsteps well known in the literature.

46. The compounds of general formula (I) wherein:

s is equal to 1;s′, s″, m, m′, m″, are 0Y is as above defined;A is selected among:i) (IIa) wherein R₁ is —H, R₂ is —C(O)NHR_(2xx) or —C(O)N(CH₃)R_(2xx)and R₂ binds a group —Y—ONO₂; and R_(a) is selected from HS—CH₂—, orR_(x)O—CH₂—, R_(x)O—CH(CH₃)—, (R_(x)O)-p-C₆H₄—CH₂—,4-(R_(x)O)-3,5-diiodobenzyl-4-(R_(x)O)-3-nitrobenzyl- wherein R_(x)—H;ii) (IIc) wherein R₁ is —H, R₂ is —C(O)NHR_(2xx) or —C(O)N(CH₃)R_(2xx)and R₂ binds a group —Y—ONO₂; and R_(a) is selected from HS—CH₂—, orR_(x)O—CH₂—, R_(x)O—CH(CH₃)—, (R_(x)O)-p-C₆H₄—CH₂—,4-(R_(x)O)-3,5-diiodobenzyl-4-(R_(x)O)-3-nitrobenzyl- wherein R_(x)—H;iii) (IIs) wherein R₁ is —H, R₃ is —H; R_(s) is selected fromR_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—,wherein R_(g) is R_(gxx)—NH— or R_(gxx)—N(CH₃)— and R_(s) binds a group—Y—ONO₂;v) (IIu) wherein R₁ is —H, R₂ is —C(O)NHR_(2xx) or —C(O)N(CH₃)R_(2xx)and R₂ binds a group —Y—ONO₂; a is 1; b is 0 or 1 and R_(x) is —H; canbe prepared as follows:

46a) by reacting a compound of formula (VIIb)

A_(3c)-Y—ONO₂  (VIIb)

wherein Y is as above defined and A_(3b) is a radical of formula (IIa),(IIc), (IIs) or (IIu) wherein R₂, a, b and R_(s) are as defined in 46;R₁ is —C(O)OC(CH₃)₃;in formula (IIs) R₃ is equal to R_(3a) wherein R_(3a) is —OTrt, whereinTrt is the trityl protecting group; in formula (IIa) and (IIc) R_(a) andR_(c) have the meanings: Trt-S—CH₂—, or R_(xa)O—CH₂—, R_(xa)O—CH(CH₃)—,(R_(xa)O)-p-C₆H₄—CH₂—,4-(R_(xa)O)-3,5-diiodobenzyl-4-(R_(xa)O)-3-nitrobenzyl- wherein R_(xa)is as above defined;In formula (IIu) R_(x) is equal to R_(xa) and is as above defined;with anhydrous or aqueous organic or inorganic acid to hydrolyze the—BOC and the other protective groups following procedure well known inthe literature.

46b) by reacting a compound of formula A₃ defined in 45b) with acompound of formula (IIIo)

A₃+W₃NH—Y^(f—ONO) ₂  (IIIo)

following the same procedure described in 7b).

47. The compounds of general formula (I) wherein:

s and m are equal to 1;s′, s″, m′, m″, are 0Y is as above defined;

B is:

A is selected among:i) (IIa) wherein R₁ is —H, R₂ is —C(O)OR_(2x) and R₂ binds a groupB—Y—ONO₂; and R_(a) is selected from HS—CH₂—, or R_(x)O—CH₂—,R_(x)O—CH(CH₃)—, (R_(x)O)-p-C₆H₄—CH₂—,4-(R_(x)O)-3,5-diiodobenzyl-4-(R_(x)O)-3-nitrobenzyl- wherein R_(x)—H;ii) (IIc) wherein R₁ is —H, R₂ is —C(O)OR_(2x) and R₂ binds a groupB—Y—ONO₂; and R_(a) is selected from HS—CH₂—, or R_(x)O—CH₂—,R_(x)O—CH(CH₃)—, (R_(x)O)-p-C₆H₄—CH₂—,4-(R_(x)O)-3,5-diiodobenzyl-4-(R_(x)O)-3-nitrobenzyl- wherein R_(x)—H;iii) (IIs) wherein R₁ is —H, R₃ is —H; R_(s) is selected fromR_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—,wherein R_(g) is R_(gx)—O—, and R_(g) binds a group B—Y—ONO₂;v) (IIu) wherein R₁ is —H, R₂ is —C(O)OR_(2x), R₂ binds a group—B—Y—ONO₂; a is 1; b is 0 or 1 and R_(x) is —H; can be prepared asfollows:

47a) by reacting a compound of formula (VIIc)

A_(3c)-Y—ONO₂  (VIIc)

wherein Y is as above defined and A_(3c) is a radical of formula (IIa),(IIc), (IIs) or (IIu) wherein R₂, a, b and R_(s) are as defined in 47;R₁ is —C(O)OC(CH₃)₃;in formula (IIs) R₃ is equal to R_(3a) wherein R_(3a) is —OTrt, whereinTrt is the trityl protecting group; in formula (IIa) and (IIc) R_(a) andR_(c) have the meanings: Trt-S—CH₂—, or R_(xa)O—CH₂—, R_(xa)O—CH(CH₃)—,(R_(xa)O)-p-C₆H₄—CH₂—,4-(R_(xa)O)-3,5-diiodobenzyl-4-(R_(xa)O)-3-nitrobenzyl- wherein R_(xa)is as above defined;In formula (IIu) R_(x) is equal to R_(xa) and is as above defined;with anhydrous or aqueous organic or inorganic acid to hydrolyze the—BOC and the other protective groups following procedure well known inthe literature.

47b) compound (VIIc) can be prepared by reacting a compound of formulaA₃ defined in 45b) with a compound of formula (IIIg) or (IIIn) dependingon the meaning of B

A₃+Hal-W₁—OC(O)O—Y—ONO₂  (IIIg)

A₃+Hal-W₁—OC(O)—Y—ONO₂  (IIIn)

following the same procedure described in 4b) or 6b).

48. The compounds of general formula (I) wherein:

s is equal to 1;s′, s″, m, m′, m″, are 0Y is as above defined;A is selected among:i) (IIa) wherein R₁ is —C(O)R_(1x), and R₁ binds a group Y—ONO₂; R₂ is—COOH; and R_(a) is selected from HS—CH₂—, or R_(x)O—CH₂—,R_(x)O—CH(CH₃)—, (R_(x)O)-p-C₆H₄—CH₂—,4-(R_(x)O)-3,5-diiodobenzyl-4-(R_(x)O)-3-nitrobenzyl- wherein R_(x)—H;ii) (IIc) wherein R₁ is —C(O)R_(1x), and R₁ binds a group Y—ONO₂; R₂ is—COOH; and R_(a) is selected from HS—CH₂—, or R_(x)O—CH₂—,R_(x)O—CH(CH₃)—, (R_(x)O)-p-C₆H₄—CH₂—,4-(R_(x)O)-3,5-diiodobenzyl-4-(R_(x)O)-3-nitrobenzyl- wherein R_(x)—H;iii) (IIs) wherein R₁ is —C(O)—R_(1x) and R₁ binds a group Y—ONO₂; R₃ is—H; R_(s) is selected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂,R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—, wherein R_(g) is —OH;v) (IIu) wherein and R₁ binds a group —Y—ONO₂; R₂ is —COOH, a is 1, b is0 or 1; R_(x) is —H;can be prepared as follows:

48a) by reacting a compound of formula (VIId)

A_(4a)-Y—ONO₂  (VIId)

wherein Y, is as above defined and A_(4a) is a radical of formula (IIa),(IIc), (IIs) or (IIu) wherein; R₁, R₂, a, b and R_(s) are as defined in48; in formula (IIs) R₃ is R_(3a) and is —OTrt; in formula (IIa) and(IIc) R_(a) and R_(c) are TrtS—CH₂—, or R_(xa)O—CH₂—, R_(xa)O—CH(CH₃)—,(R_(xa)O)-p-C₆H₄—CH₂—,4-(R_(xa)O)-3,5-diiodobenzyl-4-(R_(xa)O)-3-nitrobenzyl- wherein R_(xa)is -Trt or the group dimethyl-tert-butylsilyl; R_(x) of formula (IIu) isH or R_(xa) wherein R_(xa) is as above defined;with anhydrous or aqueous organic or inorganic acid to remove theprotective groups following procedure well known in the literature.

48b) compound (VIId) are prepared by reacting a compound of formula A₄with a compound of formula (IIIe)

A₄+Act-C(O)—Y—ONO₂  (IIIe)

Wherein Act and Y are as above defined, A₄ is a radical of formula(IIa), (IIc), (IIs) or (IIu) wherein R₁ is —H, R₂ is —COOH, a and b areas above defined in 48, R₃ is R_(3a), R_(a) and R_(c) are TrtS—CH₂—, orR_(xa)O—CH₂—, R_(xa)O—CH(CH₃)—, (R_(xa)O)-p-C₆H₄—CH₂—,4-(R_(xa)O)-3,5-diiodobenzyl-4-(R_(xa)O)-3-nitrobenzyl- wherein R_(xa)is -Trt or dimethyl-tert-butylsilyl; R_(x) of formula (IIu) is H orR_(xa) wherein R_(xa) is as above defined; R_(s) is R_(g)C(O)CH₂—NH—,R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—, wherein R_(g) is —OH;following the same procedure described in 1b′).

Compounds A₄ are commercially available.

49. The compounds of general formula (I) wherein:

s is equal to 1;s′, s″, m, m′, m″, are 0Y is as above defined;A is selected among:i) (IIa) wherein R₁ is —C(O)O—R_(1x), and R₁ binds a group Y—ONO₂; R₂ is—COOH; and R_(a) is selected from HS—CH₂—, or R_(x)O—CH₂—,R_(x)O—CH(CH₃)—, (R_(x)O)-p-C₆H₄—CH₂—,4-(R_(x)O)-3,5-diiodobenzyl-4-(R_(x)O)-3-nitrobenzyl- wherein R_(x)—H;ii) (IIc) wherein R₁ is —C(O)O—R_(1x), and R₁ binds a group Y—ONO₂; R₂is —COOH; and R_(a) is selected from HS—CH₂—, or R_(x)O—CH₂—,R_(x)O—CH(CH₃)—, (R_(x)O)-p-C₆H₄—CH₂—,4-(R_(x)O)-3,5-diiodobenzyl-4-(R_(x)O)-3-nitrobenzyl- wherein R_(x)—H;iii) (IIs) wherein R₁ is —C(O)O—R_(1x) and R₁ binds a group Y—ONO₂; R₃is —H; R_(s) is selected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂,R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—, wherein R_(g) is —OH;v) (IIu) wherein R₁ is —C(O)O—R_(1x) and R₁ binds a group —Y—ONO₂; R₂ is—COOH, a is 1, b is 0 or 1 and R_(x) is —H;can be prepared as follows:

49a) by reacting a compound of formula (VIIf)

A_(4b)-Y—ONO₂  (VIIf)

wherein Y is as above defined and A_(4b) is a radical of formula (IIa),(IIc), (IIs) or (IIu) wherein; R₁, R₂, a, b and R_(s) are as defined in49; R₃ is R_(3a), R_(a) and R_(c) are TrtS—CH₂—, or R_(xa)O—CH₂—,R_(xa)O—CH(CH₃)—, (R_(xa)O)-p-C₆H₄—CH₂—,4-(R_(xa)O)-3,5-diiodobenzyl-4-(R_(xa)O)-3-nitrobenzyl- wherein R_(xa)is -Trt or dimethyltert-butyl silyl; R_(x) of formula (IIu) is H orR_(xa) wherein R_(xa) is as above defined;with anhydrous or aqueous organic or inorganic acid to remove the Tritylor dimethyltert-butyl silyl protective groups following procedure wellknown in the literature.

49b) by reacting a compound of formula A₄ with a compound of formula(IIIf) or (IIIi)

A₄+Act-C(O)O—Y—ONO₂  (IIIf)

A₄+HO—Y—ONO₂

Wherein Act and Y are as above defined, A₄ is as defined in 48b),following the same procedure described in 3b).

50. The compounds of general formula (I) wherein:

s and s′ are equal to 1;s″, m, m′, m″, are 0Y and Y′ are equal and are as above defined;A is selected among:(IIa) wherein R₁ is —H, R₂ is —C(O)O, and R_(a) is selected fromR_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—,wherein R_(g) is R_(gx)—O—, both R₂ and R_(a) bind a group —Y—ONO₂ or agroup —Y′—ONO₂;(IIc) wherein R₁ is —H, R₂ is —C(O)O, and R_(c) is selected fromR_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—,wherein R_(g) is R_(gx)—O—, both R₂ and R_(c) bind a group —Y—ONO₂ or agroup —Y′—ONO₂;can be prepared as follows:

50a) by reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″,Y, Y′, Y″ are as above defined in 50, A is a radical of formula (IIa),(IIc), wherein; R₂, R_(a), R_(c) are as defined in 50; R₁ is—C(O)OC(CH₂)₂ with anhydrous or aqueous organic or inorganic acid tohydrolyze the —BOC protective groups following procedure well known inthe literature.

50b) by reacting a compound of formula A with a compound of formula(IIIi)

A+HO—Y—ONO₂  (IIIi)

wherein Y is as above defined and A is a radical of formula (IIa), (IIc)wherein R₁ is —C(O)OC(CH₃)₃, R₂ is —COOH, R_(a) and R_(c) are selectedfrom R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—,wherein R_(g) is —OH;following the same procedure described in 8b) using a ratio A/(IIIi) 1:2

51. The compounds of general formula (I) wherein:

s and s′ are equal to 1;s″, m, m′, m″, are 0Y and Y′ are equal and are as above defined;A is selected among:(IIa) wherein R₁ is —H, R₂ is —C(O)NHR_(2xx) or —C(O)N(CH₃)R_(2xx) andR_(a) is selected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—,R_(g)C(O)(CH₂)₄—, wherein R_(g) is R_(gxx)—NH— or R_(gxx)—N(CH₃)— andboth R₂ and R_(a) bind a group —Y—ONO₂ or a group —Y′—ONO₂;(IIc) wherein R₁ is —H, R₂ is —C(O)NHR_(2xx) or —C(O)N(CH₃)— and R_(c)is selected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—,R_(g)C(O)(CH₂)₄—, wherein R_(g) is R_(gxx)—NH— or R_(gxx)—N(CH₃)— andboth R₂ and R_(c) bind a group —Y—ONO₂ or a group —Y′—ONO₂;can be prepared as follows:

51a) by reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″,Y, Y′, Y″ are as above defined in 51, A is a radical of formula (IIa),(IIc), wherein R₂, R_(a), R_(c) are as defined in 51; R₁ is—C(O)OC(CH₃)₃ with anhydrous or aqueous organic or inorganic acid tohydrolyze the —BOC protective groups following procedure well known inthe literature.

51b) by reacting a compound of formula A with a compound of formula(IIIo)

A+W₃NH—Y—ONO₂  (IIIo)

wherein Y is as above defined, W₃ is as above defined and A is a radicalof formula (IIa), (IIc) wherein R₁ is —C(O)OC(CH₃)₃, R₂ is —COOH, R_(a)and R_(c) are selected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂,R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—, wherein R_(g) is —OH;following the same procedure described in 7b) using a ratio A/(IIIo)1:2.

52. The compounds of general formula (I) wherein:

s and s′ are equal to 1;m and m′ are equal to 1;m″ and s″ are 0

B is:

Y and Y′ are equal and are as above defined;A is selected among (IIa) and (IIc) wherein R₁ is —H and R₂ is—C(O)OR_(2x) and binds a group —B—Y—ONO₂ or —B′—Y′—ONO₂;R_(a) and R_(c) are selected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂,R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—, wherein R_(g) is R_(gx)—O—, andR_(a) and R_(c) bind one of the groups —B—Y—ONO₂ or —B′—Y′—ONO₂;Can be prepared as follows:

52a) by reacting a compound of formula (I) wherein B, s, s′, s″, m, m′,m″, Y, Y′, Y″ are as above defined in 52, A is a radical of formula(IIa) or (IIc) wherein R₁ is —C(O)OC(CH₃)₃; R₂, R_(a) and R_(c) are asdefined in 52;

with anhydrous or aqueous organic or inorganic acid to hydrolyze the—BOC protective groups following procedure well known in the literature.

52b) by reacting a compound of formula A with a compound of formula(IIIg)

A+Hal-W₁—OC(O)O—Y—ONO₂  (IIIg)

wherein Y is as above defined and A is selected from (IIa) or (IIc)wherein R₂ is —COOH and R₁ is —C(O)O(CH₃)₃;R_(a) and R_(c) are selected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂,R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—, wherein R_(g) is —OH;using a ratio A/(IIIg) 1:2 and applying the procedure described in 4b).

53. The compounds of general formula (I) wherein:

s and s′ are equal to 1;m and m′ are equal to 1;m″ and s″ are 0

B is:

Y and Y′ are equal and are as above defined;A is selected among (IIa) and (IIc) wherein R₁ is —H and R₂ is—C(O)OR_(2x) and binds a group —B—Y—ONO₂ or —B′—Y′—ONO₂;R_(a) and R_(c) are selected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂,R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—, wherein R_(g) is R_(gx)—O—, andR_(a) and R_(c) bind one of the groups —B—Y—ONO₂ or —B′—Y′—ONO₂;Can be prepared as follows:

53a) by reacting a compound of formula (I) wherein B, s, s′, s″, m, m′,m″, Y, Y′, Y″ are as above defined in 53, A is a radical of formula(IIa) or (IIc) wherein R₁ is —C(O)OC(CH₃)₃; R₂, R_(a) and R_(c) are asdefined in 53;

with anhydrous or aqueous organic or inorganic acid to hydrolyze the—BOC protective groups following procedure well known in the literature.

53b) by reacting a compound of formula A with a compound of formula(IIIn)

A+Hal-W₁—O(O)C—Y—ONO₂  (IIIn)

wherein Y is as above defined and A is selected from (IIa) or (IIc)wherein R₂ is —COOH and R₁ is —C(O)O(CH₃)₃;R_(a) and R_(c) are selected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂,R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—, wherein R_(g) is —OH;Using a ratio A/(IIIn) 1:2 and applying the procedure described in 6b).

54. The compounds of general formula (I) wherein:

s, s′ and s″ are equal to 1;m, m′, m″, are 0Y, Y′ and Y″ are as above defined with the proviso that Y is equal to Y′A is a radical of formula (IIa) or (IIc) wherein R₁ is —C(O)—R_(1x) andit binds the group —Y″—ONO₂, R₂ is —C(O)OR_(2x) and it binds the group—Y—ONO₂ or —Y′—ONO₂;R_(a) and R_(c) are selected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂,R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—, wherein R_(g) is R_(gx)O—, and R_(a)and R_(c) bind one of the groups —Y—ONO₂ or —Y′—ONO₂;can be prepared as follows:

54a) by reacting a compound of formula (I) prepared as described in 49.

with a compound of formula (IIIe):

wherein in formula (I) Y and Y′ are equal and A is a radical of formula(IIa) or (IIc) wherein R₁ is —H; R₂, R_(a) and R_(c) are as defined in54;following the same procedure described in 1b′).

55. The compounds of general formula (I) wherein:

s, s′ and s″ are equal to 1;m, m′, m″, are 0Y, Y′ and Y″ are as above defined with the proviso that Y is equal to Y′A is a radical of formula (IIa) or (IIc) wherein R₁ is —C(O)O—R_(1x) andit binds the group —Y″—ONO₂, R₂ is —C(O)OR_(2x) and it binds the group—Y—ONO₂ or —Y′—ONO₂;R_(a) and R_(c) are selected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂,R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—, wherein R_(g) is R_(gx)O—, and R_(a)and R_(c) bind one of the groups —Y—ONO₂ or —Y′—ONO₂;can be prepared as follows:

55a) by reacting a compound of formula (I) prepared as described in 49.

with a compound of formula (IIIf):

wherein in formula (I) Y and Y′ are equal and A has been already definedin 54;following the same procedure described in 3b).

56. The compounds of general formula (I) wherein:

s, s′ and s″ are equal to 1;m, m′, m″, are 0Y, Y′ and Y″ are as above defined with the proviso that Y is equal to Y′A is a radical of formula (IIa) or (IIc) wherein R₁ is —C(O)—R_(1x) andit binds the group —Y″—ONO₂, R₂ is —C(O)NHR_(2xx) or —C(O)N(CH₃)R_(2xx)and it binds the group —Y—ONO₂ or —Y′—ONO₂;R_(a) and R_(c) are selected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂,R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—, wherein R_(g) is R_(gx)NH— orR_(gx)—N(CH₃)— and R_(a) and R_(c) bind one of the groups —Y—ONO₂ or—Y′—ONO₂;can be prepared as follows:

56a) by reacting a compound of formula (I) prepared as described in 51.

with a compound of formula (IIIe):

wherein in formula (I) Y and Y′ are equal and A is a radical of formula(IIa) or (IIc) wherein R₁ is —H; R₂, R_(a) and R_(c) are as defined in56;following the same procedure described in 1b′).

57. The compounds of general formula (I) wherein:

s, s′ and s″ are equal to 1;m, m′, m″, are 0Y, Y′ and Y″ are as above defined with the proviso that Y is equal to Y′A is a radical of formula (IIa) or (IIc) wherein R₁ is —C(O)O—R_(1x) andit binds the group —Y″—ONO₂, R₂ is —C(O)NHR_(2xx) or —C(O)N(CH₃)R_(2xx)and it binds the group —Y—ONO₂ or —Y′—ONO₂;R_(a) and R_(c) are selected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂,R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—, wherein R_(g) is R_(gx)NH— orR_(gx)N(CH₃)— and R_(a) and R_(c) bind one of the groups —Y—ONO₂ or—Y′—ONO₂;can be prepared as follows: 57a) by reacting a compound of formula (I)prepared as described in 51.with a compound of formula (IIIf):

wherein in formula (I) Y and Y′ are equal and A has been already definedin 56;following the same procedure described in 3b).

58. The compounds of general formula (I) wherein:

s, s′ and s″ are equal to 1;m and m′ are equal to 1;m″ is 0;

B is:

Y, Y′ and Y″ are as above defined with the proviso that Y is equal to Y′A is a radical of formula (IIa) or (IIc) wherein R₁ is —C(O)—R_(1x) andit binds the group —Y″—ONO₂, R₂ is —C(O)OR_(2x) and it binds the groupB—Y—ONO₂ or B—Y′—ONO₂ wherein B—Y—ONO₂ or B—Y′—ONO₂ are equal;R_(a) and R_(c) are selected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂,R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—, wherein R_(g) is R_(gx)O—, and R_(a)and R_(c) bind one of the groups a group B—Y—ONO₂ or B—Y′—ONO₂ whereinB—Y—ONO₂ or B—Y′—ONO₂ are equal;can be prepared as follows:

58a) by reacting a compound of formula (I) prepared as described in 52.if B is:

or prepared in 53. if B is:

with a compound of formula (IIIe):

wherein in formula (I) B, Y and Y′ are as defined in 58; andA is a radical of formula (IIa) or (IIc) wherein R₁ is —H; R₂, R_(a) andR_(c) are as defined in 58;following the same procedure described in 1b′).

59. The compounds of general formula (I) wherein:

s, s′ and s″ are equal to 1;m and m′ are equal to 1;m″ is 0;

B is:

Y, Y′ and Y″ are as above defined with the proviso that Y is equal to Y′A is a radical of formula (IIa) or (IIc) wherein R₁ is —C(O)O—R_(1x) andit binds the group —Y″—ONO₂, R₂ is —C(O)OR_(2x) and it binds the groupB—Y—ONO₂ or B—Y′—ONO₂ wherein B—Y—ONO₂ or B—Y′—ONO₂ are equal;R_(a) and R_(c) are selected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂,R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—, wherein R_(g) is R_(gx)—O—, andR_(a) and R_(c) bind one of the groups a group B—Y—ONO₂ or B—Y′—ONO₂wherein B—Y—ONO₂ or B—Y′—ONO₂ are equal;can be prepared as follows:

59a) by reacting a compound of formula (I) prepared as described in 52.if B is:

or prepared in 53. if B is:

with a compound of formula (IIIf):

wherein in formula (I) B, Y and Y′ are as defined in 59; A is a radicalof formula (IIa) or (IIc) wherein R₁ is —H; R₂, R_(a) and R_(c) are asdefined in 59;following the same procedure described in 3b).

60. The compounds of general formula (I) wherein:

s, is equal to 1;s′, s″, m, m′ and m″ are equal to 0;Y is as above defined;A is selected from (IIa) and (IIc) wherein R₁ is —C(O)—R_(1x) and bindsa group —Y—ONO₂, R₂ is —COOH;R_(a) and R_(c) are selected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂,R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—, wherein R_(g) is —OH; can beprepared as follows:

60a) by reacting a compound of formula A with a compound of formula(IIIe)

A+Act-(O)C—Y—ONO₂  (IIIe)

wherein Y is as above defined and A is a commercially available compoundof formula (IIa) or (IIc) wherein R₂ is —COOH and R₁ is —H;R_(a) and R_(c) are selected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂,R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—, wherein R_(g) is —OH;applying the procedure described in 1b′).

61. The compounds of general formula (I) wherein:

s, is equal to 1;s′, s″, m, m′ and m″ are equal to 0;Y is as above defined;A is selected from (IIa) and (IIc) wherein R₁ is —C(O)O—R_(1x) and bindsa group —Y—ONO₂, R₂ is —COOH;R_(a) and R_(c) are selected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂,R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—, wherein R_(g) is —OH; can beprepared as follows:

61a) by reacting a compound of formula A with a compound of formula(IIIf)

A+Act-(O)C—O—Y—ONO₂  (IIIf)

wherein Y is as above defined and A is as defined in 60a) applying theprocedure described in 3b).

62. Alternatively compounds (I) described in 54. can be preparedstarting from compounds (I) prepared as described in 60. and compounds(IIIf) applying the same procedure described in 8b) using a ratio(I)/(IIIi) 1:2. In this case Y′ and Y″ are equal.

63. Alternatively compounds (I) described in 55. can be preparedstarting from compounds (I) prepared as described in 61. and compounds(IIIi) applying the same procedure described in 8b) using a ratio(I)/(IIIi) 1:2. In this case Y′ and Y″ are equal.

64. Alternatively compounds (I) described in 56. can be preparedstarting from compounds (I) prepared as described in 60. and compounds(IIIo) applying the same procedure described in 7b) using a ratio(I)/(IIIo) 1:2. In this case Y′ and Y″ are equal.

65. Alternatively compounds (I) described in 57. can be preparedstarting from compounds (I) prepared as described in 61. and compounds(IIIo) applying the same procedure described in 7b) using a ratio(I)/(IIIo) 1:2. In this case Y′ and Y″ are equal.

66. Alternatively compounds (I) described in 58. can be preparedstarting from compounds (I) prepared as described in 60. and compounds(IIIg) or (IIIn) depending on the meaning of B, and applying the sameprocedure described in 4b) or 6b) using a ratio (I)/(IIIg) or (I)/(IIIn)1:2. In this case Y′ and Y″ are equal.

67. Alternatively compounds (I) described in 59. can be preparedstarting from compounds (I) prepared as described in 61. and compounds(IIIg) or (IIIn) depending on the meaning of B, and applying the sameprocedure described in 4b) or 6b) using a ratio (I)/(IIIg) or (I)/(IIIn)1:2. In this case Y′ and Y″ are equal.

68. The compounds of general formula (I) wherein:

s is equal to 1;s′, s″, m, m′, m″, are 0Y is as above defined;A is selected among:(IIa) wherein R₁ is —H, R₂ is —C(O)OR_(2x) and R₂ binds a group —Y—ONO₂;R_(a) is selected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—,R_(g)C(O)(CH₂)₄—, wherein R_(g) is —OH;(IIc) wherein R₁ is —H, R₂ is —C(O)OR_(2x) and R₂ binds a group —Y—ONO₂;R_(a) is selected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—,R_(g)C(O)(CH₂)₄—, wherein R_(g) is —OH; can be prepared as follows:

68a) by reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″,Y, Y′, Y″ are as above defined in 68, A is a radical of formula (IIa),(IIc), wherein R₂ is as above defined in 68; R₁ is —C(O)OC(CH₃)₃; R_(a)and R_(c) are R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—,R_(g)C(O)(CH₂)₄—, wherein R_(g) is —C(O)OC(CH₃)₃;

with anhydrous or aqueous organic or inorganic acid to hydrolyze thetert-butyl esters and the —BOC protective groups following procedurewell known in the literature.

68b) by reacting a compound of formula A with a compound of formula(IIIi)

A+HO—Y—ONO₂  (IIIi)

wherein Y is as above defined and A is a compound of formula (IIa) or(IIc) wherein R₁ is —C(O)OC(CH₃)₃, R₂ is —COOH, R_(a) and R_(c) areselected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—,R_(g)C(O)(CH₂)₄—, wherein R_(g) is —C(O)OC(CH₃)₃;following the same procedure described in 8b). Compounds A arecommercially available.

69. The compounds of general formula (I) wherein:

s is equal to 1;s′, s″, m, m′, m″, are 0Y is as above defined;A is a radical of formula(IIa) wherein R₁ is —H, R₂ is —C(O)NHR_(2xx) or —C(O)N(CH₃)R_(2xx) andR₂ binds a group —Y—ONO₂; R_(a) is selected from R_(g)C(O)CH₂—NH—,R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—, wherein R_(g) is —OH;or(IIc) wherein R₁ is —H, R₂ is —C(O)NHR_(2xx) or —C(O)N(CH₃)R_(2xx) andR₂ binds a group —Y—ONO₂; R_(c) is selected from R_(g)C(O)CH₂—NH—,R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—, wherein R_(g) is —OH;can be prepared as follows:

69a) by reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″,Y, Y′, Y″ are as above defined in 69, A is a radical of formula (IIa),(IIc), wherein R₂ is as above defined in 69; R₁ is —C(O)OC(CH₃)₃; R_(a)and R_(c) are R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—,R_(g)C(O)(CH₂)₄—, wherein R_(g) is —C(O)OC(CH₃)₃;

with anhydrous or aqueous organic or inorganic acid to hydrolyze thetert-butyl esters and the —BOC protective groups following procedurewell known in the literature.

69b) by reacting a compound of formula A with a compound of formula(IIIo)

A+W₃NH—Y—ONO₂  (IIIo)

wherein Y is as above defined, W₃ is as above defined and A is asdefined in 68b),following the same procedure described in 7b).

70. The compounds of general formula (I) wherein:

s and m are equal to 1;s′, s″, m′, m″, are 0Y is as above defined;

B is:

A is a radical selected among:(IIa) wherein R₁ is —H, R₂ is —C(O)OR_(2x) and R₂ binds a group—B—Y—ONO₂; R_(a) is selected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂,R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—, wherein R_(g) is —OH;(IIc) wherein R₁ is —H, R₂ is —C(O)OR_(2x) and R₂ binds a group—B—Y—ONO₂; R_(c) is selected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂,R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—, wherein R_(g) is —OH; can beprepared as follows:

70a) by reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″,B, Y, Y′, Y″ are as above defined in 70, A is a radical of formula(IIa), (IIc), wherein R₂ is as above defined in 70; R₁ is —C(O)OC(CH₃)₃;R_(a) and R_(c) are R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—,R_(g)C(O)(CH₂)₄—, wherein R_(g) is —C(O)OC(CH₃)₃;

with anhydrous or aqueous organic or inorganic acid to hydrolyze thetert-butyl esters and the —BOC protective groups following procedurewell known in the literature.

70b) by reacting a compound of formula A with a compound of formula(IIIg) or (IIIn) depending on the meaning of B

A+Hal-W₁—OC(O)O—Y—ONO₂  (IIIg)

A+Hal-W₁—OC(O)—Y—ONO₂  (IIIn)

wherein Y, Hal, W₁ are as above defined and A is as defined in 68b),following the same procedures described in 4b) or 6b).

71. The compounds of general formula (I) wherein:

s is equal to 1;s′, s″, m, m′, m″, are 0Y is as above defined;A is selected among:(IIa) wherein R₁ is —H, R₂ is —COOH; R_(a) is selected fromR_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—,wherein R_(g) is R_(gx)—O—, and R_(a) binds a group —Y—ONO₂;(IIc) wherein R₁ is —H, R₂ is —COOH; R_(a) is selected fromR_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—,wherein R_(g) is R_(gx)—O—, and R_(a) binds a group —Y—ONO₂,can be prepared as follows:

71a) by reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″,Y, Y′, Y″ are as above defined in 71, A is a radical of formula (IIa),(IIc), R_(a) and R_(c) are as above defined in 71; R₁ is —C(O)OC(CH₃)₃;R₂ is —C(O)OC(CH₃)₃;

with anhydrous or aqueous organic or inorganic acid to hydrolyze thetert-butyl esters and the —BOC protective groups following procedurewell known in the literature.

68b) by reacting a compound of formula A with a compound of formula(IIIi)

A+HO—Y—ONO₂  (IIIi)

wherein Y is as above defined and A is a radical of formula (IIa), (IIc)wherein R₁ is —C(O)OC(CH₃)₃, R₂ is —C(O)OC(CH₃)₃, R_(a) and R_(c) areselected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—,R_(g)C(O)(CH₂)₄—, wherein R_(g) is —OH;following the same procedure described in 8b).

Compounds A are commercially available.

72. The compounds of general formula (I) wherein:

s is equal to 1;s′, s″, m, m′, m″, are 0Y is as above defined;A is selected among:(IIa) wherein R₁ is —H, R₂ is —COOH; R_(a) is selected fromR_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—,wherein R_(g) is R_(gxx)—NH— or R_(gxx)—N(CH₃)— and R_(a) binds a group—Y—ONO₂;(IIc) wherein R₁ is —H, R₂ is —COOH; R_(a) is selected fromR_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—,wherein R_(g) is R_(gxx)—NH— or R_(gxx)—N(CH₃)— and R_(c) binds a group—Y—ONO₂;can be prepared as follows:

72a) by reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″,Y, Y′, Y″ are as above defined in 72, A is a radical of formula (IIa),(IIc), wherein R_(a) and R_(c) are as above defined in 71; R₁ is—C(O)OC(CH₃)₃; R₂ is —C(O)OC(CH₃)₃;

with anhydrous or aqueous organic or inorganic acid to hydrolyze thetert-butyl esters and the —BOC protective groups following procedurewell known in the literature.

72b) by reacting a compound of formula A with a compound of formula(IIIo):

A+W₃NH—Y—ONO₂  (IIIo)

wherein Y and W₃ are as above defined and A is as defined in 71b)following the same procedure described in 7b).

73. The compounds of general formula (I) wherein:

s and m are equal to 1;s′, s″, m′, m″, are 0Y is as above defined;

B is:

A is selected among:(IIa) wherein R₁ is —H, R₂ is —COOH; R_(a) is selected fromR_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—,wherein R_(g) is R_(gx)—O—, and R_(a) binds a group —B—Y—ONO₂;(IIc) wherein R₁ is —H, R₂ is —COOH; R_(a) is selected fromR_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—,wherein R_(g) is R_(gx)—O—, and R_(c) binds a group B—Y—ONO₂;can be prepared as follows:

73a) by reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″,B, Y, Y′, Y″ are as above defined in 73, A is a radical of formula(IIa), (IIc), wherein R_(a) and R_(c) are as above defined in 71; R₁ is—C(O)OC(CH₃)₃; R₂ is —C(O)OC(CH₃)₃;

with anhydrous or aqueous organic or inorganic acid to hydrolyze thetert-butyl esters and the —BOC protective groups following procedurewell known in the literature.

73b) by reacting a compound of formula A with a compound of formula(IIIg) or (IIIn) depending on the meaning of B

A+Hal-W₁—OC(O)O—Y—ONO₂  (IIIg)

A+Hal-W₁—OC(O)—Y—ONO₂  (IIIn)

wherein Y, Hal, W₁ are as above defined and A is as defined in 71b),following the same procedures described in 4b) or 6b).

74. The compounds of general formula (I) wherein:

s and s′ are equal to 1;s″, m, m′, m″, are 0Y and Y′ can be equal or different and are as above defined;A is selected among:(IIa) wherein R₁ is —C(O)—R_(1x) and binds a group —Y′—ONO₂; R₂ is—C(O)OR_(2x) and binds a group —Y—ONO₂; R_(a) is selected fromR_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—,wherein R_(g) is —OH;(IIc) wherein R₁ is —C(O)—R_(1x) and binds a group —Y′—ONO₂; R₂ is—C(O)OR_(2x) and binds a group —Y—ONO₂; R_(a) is selected fromR_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—,wherein R_(g) is —OH;can be prepared as follows:

74a) by reacting a compound of formula (I) prepared as described in 68.with a compound of formula (IIIe):

wherein Act, Y and Y′ are as above defined and A is a radical of formula(IIa), (IIc), wherein R₁ is —H, R₂ is —C(O)OR_(2x) and binds a group—Y—ONO₂; R_(a) and R_(c) are selected from R_(g)C(O)CH₂—NH—,R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—, wherein R_(g) is —OH;following the same procedures described in 1b′).

75. The compounds of general formula (I) wherein:

s and s′ are equal to 1;s″, m, m′, m″, are 0Y and Y′ can be equal or different and are as above defined;A is selected among:(IIa) wherein R₁ is —C(O)O—R_(1x) and binds a group —Y′—ONO₂; R₂ is—C(O)OR_(2x) and binds a group —Y—ONO₂; R_(a) is selected fromR_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—,wherein R_(g) is —OH;(IIc) wherein R₁ is —C(O)O—R_(1x) and binds a group —Y′—ONO₂; R₂ is—C(O)OR_(2x) and binds a group —Y—ONO₂; R_(a) is selected fromR_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—,wherein R_(g) is —OH;can be prepared as follows:

75a) by reacting a compound of formula (I) prepared as described in 68.with a compound of formula (IIIf):

wherein Act, Y and Y′ are as above defined and A is as defined in 74a);following the same procedures described in 3b).

76. The compounds of general formula (I) wherein:

s and s′ are equal to 1;s″, m, m′, m″, are 0Y and Y′ can be equal or different and are as above defined;A is selected among:(IIa) wherein R₁ is —C(O)—R_(1x) and binds a group —Y′—ONO₂; R₂ is—C(O)NHR_(2xx) or —C(O)N(CH₃)R_(2xx) and binds a group —Y—ONO₂; R_(a) isselected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—,R_(g)C(O)(CH₂)₄—, wherein R_(g) is —OH;(IIc) wherein R₁ is —C(O)—R_(1x) and binds a group —Y′—ONO₂; R₂ is—C(O)NHR_(2xx) or —C(O)N(CH₃)R_(2xx) and binds a group —Y—ONO₂; R_(a) isselected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—,R_(g)C(O)(CH₂)₄—, wherein R_(g) is —OH; can be prepared as follows:

76a) by reacting a compound of formula (I) prepared as described in 69.with a compound of formula (IIIe):

wherein Act, Y and Y′ are as above defined and A is a radical of formula(IIa), (IIc), wherein R₁ is —H, R₂ is —C(O)NHR_(2xx) or—C(O)N(CH₃)R_(2xx) and binds a group —Y—ONO₂; R_(a) and R_(c) areselected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—,R_(g)C(O)(CH₂)₄—, wherein R_(g) is —OH;following the same procedures described in 1b′).

77. The compounds of general formula (I) wherein:

s and s′ are equal to 1;s″, m, m′, m″, are 0Y and Y′ can be equal or different and are as above defined;A is selected among:(IIa) wherein R₁ is —C(O)O—R_(1x) and binds a group —Y′—ONO₂; R₂ is—C(O)NHR_(2xx) or —C(O)N(CH₃)R_(2xx) and binds a group —Y—ONO₂; R_(a) isselected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—,R_(g)C(O)(CH₂)₄—, wherein R_(g) is —OH;(IIc) wherein R₁ is —C(O)O—R_(1x) and binds a group —Y′—ONO₂; R₂ is—C(O)NHR_(2xx) or —C(O)N(CH₃)R_(2xx) and binds a group —Y—ONO₂; R_(a) isselected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—,R_(g)C(O)(CH₂)₄—, wherein R_(g) is —OH; can be prepared as follows:

77a) by reacting a compound of formula (I) prepared as described in 69.with a compound of formula (IIIf):

wherein Act, Y and Y′ are as above defined and A is as above defined in76, following the same procedures described in 3b).

78. The compounds of general formula (I) wherein:

s, s′ and m are equal to 1;s″, m′, m″, are 0Y and Y′ can be equal or different and are as above defined;

B is:

A is selected among:(IIa) wherein R₁ is —C(O)—R_(1x) and binds a group —Y′—ONO₂; R₂ is—C(O)OR_(2x) and binds a group —B—Y—ONO₂; R_(a) is selected fromR_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—,wherein R_(g) is —OH;(IIc) wherein R₁ is —C(O)—R_(1x) and binds a group —Y′—ONO₂; R₂ is—C(O)OR_(2x) and binds a group —B—Y—ONO₂; R_(x) is selected fromR_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—,wherein R_(g) is —OH; can be prepared as follows:

78a) by reacting a compound of formula (I) prepared as described in 70.with a compound of formula (IIIe):

wherein Act, B, Y and Y′ are as above defined and A is a radical offormula (IIa), (IIc), wherein R₁ is —H, R₂ is —C(O)OR_(2x) and binds agroup B—Y—ONO₂; R_(a) and R_(c) are selected from R_(g)C(O)CH₂—NH—,R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—, wherein R_(g) is —OH;following the same procedures described in 1b′).

79. The compounds of general formula (I) wherein:

s, s′ and m are equal to 1;s″, m′, m″, are 0Y and Y′ can be equal or different and are as above defined;

B is:

A is selected among:(IIa) wherein R₁ is —C(O)O—R_(1x) and binds a group —Y′—ONO₂; R₂ is—C(O)OR_(2x) and binds a group —B—Y—ONO₂; R_(a) is selected fromR_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—,wherein R_(g) is —OH;(IIc) wherein R₁ is —C(O)O—R_(1x) and binds a group —Y′—ONO₂; R₂ is—C(O)OR_(2x) and binds a group —B—Y—ONO₂; R_(a) is selected fromR_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—,wherein R_(g) is —OH; can be prepared as follows:

79a) by reacting a compound of formula (I) prepared as described in 70.with a compound of formula (IIIf):

wherein Act, B, Y and Y′ are as above defined and A is as defined in78a), following the same procedures described in 3b).

80. The compounds of general formula (I) wherein:

s and s′ are equal to 1;s″, m, m′, m″, are 0Y and Y′ can be equal or different and are as above defined;A is selected among:(IIa) wherein R₁ is —C(O)—R_(1x) and it binds a group —Y′—ONO₂; R₂ is—COOH; R_(a) is selected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂,R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—, wherein R_(g) is R_(gx)—O—, andR_(a) binds a group —Y—ONO₂ (IIc) wherein R₁ is —C(O)—R_(1x) and binds agroup —Y′—ONO₂; R₂ is —COOH; R_(c) is selected from R_(g)C(O)CH₂—NH—,R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—, wherein R_(g) isR_(gx)—O—, and R_(c) binds a group —Y—ONO₂;can be prepared as follows:

80a) by reacting a compound of formula (I) prepared as described in 71.with a compound of formula (IIIe):

wherein Act, Y and Y′ are as above defined and A is a radical of formula(IIa), (IIc), wherein R₁ is —H, R₂ is —COOH; R_(a) and R_(c) areselected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—,R_(g)C(O)(CH₂)₄—, wherein R_(g) is R_(gx)—O—, and R_(a) and R_(c) bind agroup —Y—ONO₂following the same procedures described in 1b′).

81. The compounds of general formula (I) wherein:

s and s′ are equal to 1;s″, m, m′, m″, are 0Y and Y′ can be equal or different and are as above defined;A is selected among:(IIa) wherein R₁ is —C(O)O—R_(1x) and it binds a group —Y′—ONO₂; R₂ is—COOH; R_(a) is selected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH_(2f)R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—, wherein R_(g) is R_(gx)—O—, andR_(a) binds a group —Y—ONO₂(IIc) wherein R₁ is —C(O)O—R_(1x) and binds a group —Y′—ONO₂; R₂ is—COOH; R_(a) is selected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂,R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—, wherein R_(g) is R_(gx)—O—, andR_(c) binds a group —Y—ONO₂;can be prepared as follows:

81a) by reacting a compound of formula (I) prepared as described in 71.with a compound of formula (IIIf):

wherein Act, Y and Y′ are as above defined and A is a radical of formula(IIa), (IIc), wherein R₁ is —H, R₂ is —COOH; R_(a) and R_(c) areselected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—,R_(g)C(O)(CH₂)₄—, wherein R_(g) is R_(gx)O— and R_(a) and R_(c) bind agroup —Y—ONO₂, following the same procedures described in 3b).

82. The compounds of general formula (I) wherein:

s and s′ are equal to 1;s″, m, m′, m″, are 0Y and Y′ can be equal or different and are as above defined;A is selected among:(IIa) wherein R₁ is —C(O)—R_(1x) and it binds a group —Y′—ONO₂; R₂ is—COOH; R_(a) is selected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂,R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—, wherein R_(g) is R_(gxx)—NH— orR_(gxx)—N(CH₃)— and R_(a) binds a group —Y—ONO₂(IIc) wherein R₁ is —C(O)—R_(1x) and it binds a group —Y′—ONO₂; R₂ is—COOH; R_(a) is selected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂,R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—, wherein R_(g) is R_(gxx)—NH— orR_(gxx)—N(CH₃)— and R_(c) binds a group —Y—ONO₂;can be prepared as follows:

82a) by reacting a compound of formula (I) prepared as described in 72.with a compound of formula (IIIe):

wherein Act, Y and Y′ are as above defined and A is a radical of formula(IIa), (IIc), wherein R₁ is —H, R₂ is —COOH; R_(a) and R_(c) areselected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—,R_(g)C(O)(CH₂)₄—, wherein R_(g) is R_(gxx)—NH— or R_(gxx)—N(CH₃)— andR_(a) and R_(c) bind a group —Y—ONO₂following the same procedures described in 1b′).

83. The compounds of general formula (I) wherein:

s and s′ are equal to 1;s″, m, m′, m″, are 0Y and Y′ can be equal or different and are as above defined;A is selected among:(IIa) wherein R₁ is —C(O)O—R_(1x) and binds a group —Y′—ONO₂; R₂ is—COOH; R_(a) is selected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂,R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—, wherein R_(g) is R_(gxx)—NH— orR_(gxx)—N(CH₃)— and R_(a) binds a group —Y—ONO₂(IIc) wherein R₁ is —C(O)O—R_(1x) and binds a group —Y′—ONO₂; R₂ is—COOH; R_(c) is selected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂,R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—, wherein R_(g) is R_(gxx)—NH— orR_(gxx)—N(CH₃)— and R_(c) binds a group —Y—ONO₂;can be prepared as follows:

83a) by reacting a compound of formula (I) prepared as described in 72.with a compound of formula (IIIf):

wherein Act, Y and Y′ are as above defined and A is as defined in 82a),following the same procedures described in 3b).

84. The compounds of general formula (I) wherein:

s, s′and m are equal to 1;s″, m′, m″, are 0Y and Y′ can be equal or different and are as above defined;

B is:

A is selected among:(IIa) wherein R₁ is —C(O)—R_(1x) and binds a group —Y′—ONO₂; R₂ is—COOH; R_(a) is selected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂,R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—, wherein R_(g) is R_(gx)—O—, andR_(a) binds a group —B—Y—ONO₂;(IIc) wherein R₁ is —C(O)—R_(1x) and binds a group —Y′—ONO₂; R₂ is—COOH; R_(c) is selected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂,R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—, wherein R_(g) is R_(gx)—O—, andR_(c) binds a group —B—Y—ONO₂;can be prepared as follows:

84a) by reacting a compound of formula (I) prepared as described in 73.with a compound of formula (IIIe):

wherein Act, B, Y and Y′ are as above defined and A is a radical offormula (IIa), (IIc), wherein R₁ is —H, R₂ is —COOH; R_(a) and R_(c) areselected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—,R_(g)C(O)(CH₂)₄—, wherein R_(g) is R_(gx)O— and R_(a) and R_(c) bind agroup B—Y—ONO₂;following the same procedures described in 1b′).

85. The compounds of general formula (I) wherein:

s, s′and m are equal to 1;s″, m′, m″, are 0Y and Y′ can be equal or different and are as above defined;

B is:

A is selected among:(IIa) wherein R₁ is —C(O)O—R_(1x) and binds a group —Y′—ONO₂; R₂ is—COOH; R_(a) is selected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂,R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—, wherein R_(g) is R_(gx)—O—, andR_(a) binds a group —B—Y—ONO₂;(IIc) wherein R₁ is —C(O)O—R_(1x) and it binds a group —Y′—ONO₂; R₂ is—COOH; R_(c) is selected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂,R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—, wherein R_(g) is R_(g)O— and R_(c)binds a group —B—Y—ONO₂;can be prepared as follows:

85a) by reacting a compound of formula (I) prepared as described in 73.with a compound of formula (IIIf):

wherein Act, B, Y and Y′ are as above defined and A is as defined in84a), following the same procedures described in 3b).

86. The compounds of general formula (I) wherein:

s and s′ are equal to 1;s″, m, m′ and m″ are equal to 0;Y and Y′ are equal and are as above defined;A is selected from (IIa), (IIc) or (IIt) wherein R₁ is —C(O)—R_(1x) andit binds a group —Y—ONO₂ or a group —Y′—ONO₂, R₂ is —COOH;R_(a) of formula (IIa) and R_(c) of formula (IIc) are R_(h)NH(CH₂)_(p)—wherein p is an integer from 0 to 4, or R_(i)NH(═NH)NH—(CH₂)₃—, andR_(h) and R_(i) are R_(hh)—C(O)— or R_(ii)—C(O) and R_(a) and R_(c) binda group —Y—ONO₂ or a group —Y′—ONO₂;in formula (IIt) R₁ is —C(O)—R_(1x) and it binds a group —Y—ONO₂ or agroup —Y′—ONO₂, R₂ is —COOH; d is 2 d′ is 1, R_(t) is —C(O)—R_(tt) andit binds a group —Y—ONO₂ or a group —Y′—ONO₂;can be prepared as follows:

86a) by reacting a compound of formula A with a compound of formula(IIIe)

A+Act-(O)C—Y—ONO₂  (IIIe)

wherein Act and Y are as above defined and A is a compound of formula(IIa), (IIc) or (IIt) wherein R₁ is —H and R₂ is —COOH;R_(a) of formula (IIa) and R_(c) of formula (IIc) are R_(h)NH(CH₂)_(p)—wherein p is an integer from 0 to 4, or R_(i)NH(═NH)NH—(CH₂)₃—, andR_(h) and R_(i) are —H;in formula (IIt) R₁ is —H, R₂ is —COOH, d is 2 d′ is 1, R_(t) is —H;using a ratio A/(IIIe) 1:2 and applying the same procedure described in1b′). Compounds A are commercially available.

87. The compounds of general formula (I) wherein:

s and s′ are equal to 1;s″, m, m′ and m″ are equal to 0;Y and Y′ are equal and are as above defined;A is a radical selected from (IIa), (IIc) and (IIt) wherein R₁ is—C(O)O—R_(1x) and binds a group —Y—ONO₂ or a group —Y′—ONO₂, R₂ is—COOH;R_(a) of formula (IIa) and R_(c) of formula (IIc) are R_(h)NH(CH₂)_(p)—wherein p is an integer from 0 to 4, or R_(i)NH(═NH)NH—(CH₂)₃—, andR_(h) and R_(i) are R_(hh)—OC(O) or R_(ii)—OC(O)— and R_(a) and R_(c)bind a group —Y—ONO₂ or a group —Y′—ONO₂;in formula (IIt) R₁ is —C(O)O—R_(1x) and binds a group —Y—ONO₂ or agroup —Y′—ONO₂, R₂ is —COOH;d is 2 d′ is 1, R_(t) is —C(O)O—R_(tt) and binds a group —Y—ONO₂ or agroup —Y′—ONO₂;can be prepared as follows:

87a) by reacting a compound of formula A with a compound of formula(IIIf)

A+Act-(O)C—O—Y—ONO₂  (IIIf)

wherein Act and Y are as above defined and A is as defined in 86a) usinga ratio A/(IIIf) 1:2 and applying the same procedure described in 3b).

88. The compounds of general formula (I) wherein:

s is equal to 1;s′, s″, m, m′ and m″ are equal to 0;Y is as above defined;A is a radical of formula (IIa), (IIc) or (IIt) wherein R₁ is —H, R₂ is—C(O)OR_(2x) and it binds a group —Y—ONO₂R_(a) of formula (IIa) and R_(c) of formula (IIc) are the groupsR_(h)NH(CH₂)_(p)— wherein p is an integer from 0 to 4,R_(i)NH(═NH)NH—(CH₂)₃—, R_(h) and R_(i) are —H;in formula (IIt) R₁ is —H, and R₂ is —C(O)OR_(2x) and it binds a group—Y—ONO₂; d is 2 d′ is 1, R_(t) is —H;can be obtained as follows:

88a) R_(a)=R_(c) selected from R_(h)NH(CH₂)_(p)— wherein p is an integerfrom 0 to 4, R_(h) is —H:

by reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″, Y,Y′, Y″ are as above defined in 88. A is a radical of (IIa), (IIc) or(IIt) wherein R₁ is —C(O)OC(CH₃)₃; R₂ is —CO(O)R_(2x) and bind; R_(a) offormula (IIa) and R_(c) of formula (IIc) are selected fromR_(h)NH(CH₂)_(p)— wherein p is an integer from 0 to 4, R_(h) is—C(O)OC(CH₃)₃;in formula (IIt) R₁ and R₂ are as above defined d is 2 d′ is 1, R_(t) is—C(O)OC(CH₃)₃;with anhydrous or aqueous organic or inorganic acid to hydrolyze the—BOC protective groups following procedure well known in the literature.

88a′) R_(a)=R_(c) selected from R_(i)NH(═NH)NH—(CH₂)₃—, R_(i) is —H:

by reacting a compound of formula (VIIa)

A_(5a)-Y—ONO₂  (VIIIa)

wherein Y, is as above defined; A_(5a) is a radical of formula (IIa),(IIc) wherein R₁ is —C(O)OC(CH₃)₃; R₂ is —CO(O)R_(2x); R_(a) of formula(IIa) and R_(c) of formula (IIc) are R_(ia)—NH(═NH)NH—(CH₂)₃— whereinR_(ia) is the known protective group —Pbf(2,2,4,6,7-pentamethyl-dihydrobenzofuran-5-sulfonyl)-;with anhydrous or aqueous organic or inorganic acid to hydrolyze the—BOC and the —Pbf protective groups following procedure well known inthe literature.

88b) compounds described in 88a) and 88a′) can be respectively obtainedby reacting a compound of formula A or A₅ with a compound of formula(IIIi)

wherein Y is as above defined and:A is a radical of formula (IIa), (IIc) or (IIt) wherein R₁ is—C(O)OC(CH₃)₃; R₂ is —COOH; R_(a) and R_(c) are R_(h)NH(CH₂)_(p)—wherein p as above defined and R_(h) is —C(O)OC(CH₃)₃; d and d′ are asabove defined, and R_(t) is —C(O)OC(CH₃)₃;A₅ is a radical of formula (IIa) or (IIc) wherein R₁ is —C(O)OC(CH₃)₃;R₂ is —COOH; R_(a) and R_(c) are R_(ia)NH(═NH)NH—(CH₂)₃— wherein R_(ia)is as above defined using the same procedure described in 8b).

Compounds A and A₅ as above defined are commercially available or can beeasily obtained from commercially available compounds by simpledeprotection/protection steps as known in the literature.

89. The compounds of general formula (I) wherein:

s is equal to 1;s′, s″, m, m′ and m″ are equal to 0;Y is as above defined;A is a radical of formula (IIa), (IIc) or (IIt) wherein R₁ is —H, R₂ is—C(O)NHR_(2xx) or —C(O)N(CH₃)R_(2xx) and it binds a group —Y—ONO₂;R_(a) of formula (IIa) and R_(c) of formula (IIc) are R_(h)NH(CH₂)_(p)—wherein p is an integer from 0 to 4, or R_(i)NH(═NH)NH—(CH₂)₃—, andR_(h) and R_(i) are —H;in formula (IIt) R₁ is —H, R₂ is —C(O)NHR_(2xx) or —C(O)N(CH₃)R_(2xx)and it binds a group —Y—ONO₂; d is 2 d′ is 1, R_(t) is —H;can be obtained as follows:

89a) R_(a)=R_(c) are selected from R_(h)NH(CH₂)_(p)— wherein p is aninteger from 0 to 4, R_(h) is —H:

by reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″, Y,Y′, Y″ are as above defined in 89. A is a radical of formula (IIa),(IIc) or (IIt) wherein R₁ is —C(O)OC(CH₃)₃; R₂ is —C(O)NHR_(2xx) or—C(O)N(CH₃)R_(2xx); R_(a), R^(c), p, d, d′, R_(h) and R_(t) are asdefined in 88a) with anhydrous or aqueous organic or inorganic acid tohydrolyze the —BOC protective groups.

89a′) R_(a)=R_(c) selected from R_(i)NH(═NH)NH—(CH₂)₃—, R_(i) is —H:

by reacting a compound of formula (VIIIb):

A₆-Y—ONO₂  (VIIIb)

wherein Y, is as above defined; A₆ is a radical of formula (IIa), (IIc)wherein R₁ is —C(O)OC(CH₃)₃; R₂ is —C(O)NHR_(2xx) or —C(O)N(CH₃)R_(2xx);R_(a) of formula (IIa) and R_(c) of formula (IIc) areR_(ia)—NH(═NH)NH—(CH₂)₃— wherein R_(ia) is the —Pbf group as abovedefined;with anhydrous or aqueous organic or inorganic acid to hydrolyze the—BOC and the —Pbf protective groups following procedure well known inthe literature.

89b) compounds described in 89a) and 89a′) can be respectively obtainedby reacting a compound of formula A or a compound of formula A₅ alreadydefined in 88b) with a compound of formula (IIIo)

using the same procedure described in 7b).

90. The compounds of general formula (I) wherein:

s and m are equal to 1;s′, s″, m′ and m″ are equal to 0;Y is as above defined;

B is:

A is a radical of formula (IIa), (IIc) or (IIt) wherein R₁ is —H, R₂ is—C(O)OR_(2x) and binds a group —B—Y—ONO₂;R_(a) of formula (IIa) and R_(c) of formula (IIc) are R_(h)NH(CH₂)_(p)—wherein p is an integer from 0 to 4, or R_(i)NH(═NH)NH—(CH₂)₃—, andR_(h) and R_(i) are —H;in formula (IIt) R₁ is —H, and R₂ is —C(O)OR_(2x) and binds a group—B—Y—ONO₂, d is 2 d′ is 1, R_(t) is —H;can be obtained as follows:

90a) R_(a)=R_(c) selected from R_(h)NH(CH₂)_(p)— wherein p is an integerfrom 0 to 4, R_(h) is —H:

by reacting a compound of formula (I) wherein B, s, s′, s″, m, m′, m″,Y, Y′, Y″ are as above defined in 90. A is a radical of formula (IIa),(IIc) or (IIt) wherein R₁ is —C(O)OC(CH₃)₃; R₂ is —C(O)OR_(2x); B,R_(a), R_(c), p, d, R_(h) and R_(t) are as defined in 90. with anhydrousor aqueous organic or inorganic acid to hydrolyze the —BOC protectivegroups.

90a′) R_(a)=R_(c) selected from R_(i)NH(═NH)NH—(CH₂)₃—, R_(i) is —H:

by reacting a compound of formula (VIIIc):

A_(5a)-B—Y—ONO_(2 (VIIIc))

wherein B, and Y, are as above defined in 90. and A_(5a) is as definedin 88a′) with anhydrous or aqueous organic or inorganic acid tohydrolyze the —BOC and the —Pbf protective groups following procedurewell known in the literature.

90b) compounds described in 90a) and 90a′) can be respectively obtainedby reacting a compound of formula A or a compound of formula A₅ alreadydefined in 88b) with compounds (IIIg) or (IIIn) depending on the meaningof B, and applying the same procedure described in 4b) or 6b):

91. The compounds of general formula (I) wherein:

s and s′ are equal to 1;s″, m, m′ and m″ are equal to 0;Y and Y′ can be equal or different and are as above defined;A is selected from (IIa), (IIc) and (IIt) wherein R₁ is —C(O)—R_(1x) andbinds a group —Y′—ONO₂, R₂ is —C(O)OR_(2x) and binds a group —Y—ONO₂;R_(a) of formula (IIa) and R_(c) of formula (IIc) are R_(h)NH(CH₂)_(p)—wherein p is an integer from 0 to 4, or R_(i)NH(═NH)NH—(CH₂)₃—, andR_(h) and R_(i) are —H;in formula (IIt) R₁ is —C(O)—R_(1x) and it binds a group —Y^(f-)ONO₂, R₂is —C(O)OR_(2x) and R₂ binds a group —Y—ONO₂; d is 2 d′ is 1, R_(t) is—H;can be obtained as follows:

91a) R_(a)=R_(c) selected from R_(h)NH(CH₂)_(p)— wherein p is an integerfrom 0 to 4, R_(h) is —H:

by reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″, Y,Y′, Y″ are as above defined in 91. A is a radical of (IIa), (IIc) or(IIt) wherein R₁ is —C(O)—R_(1x); R₂ is —C(O)OR_(2x);R_(a) of formula (IIa) and R_(c) of formula (IIc) are selected fromR_(h)NH(CH₂)_(p)— wherein p is an integer from 0 to 4, R_(h) is—C(O)OC(CH₃)₃;in formula (IIt) R₁ and R₂ are as above defined d is 2 d′ is 1, R_(t) is—C(O)OC(CH₃)₃;with anhydrous or aqueous organic or inorganic acid to hydrolyze the—BOC protective groups following procedure well known in the literature.

91a′) R_(a)=R_(c) selected from R_(i)NH(═NH)NH—(CH₂)₃—, R_(i) is —H:

by reacting a compound of formula (VIIId)

wherein Y and Y′ are as above defined; A_(7a) is a radical of formula(IIa), (IIc) wherein R₁ is —C(O)—R_(1x); R₂ is CO(O); R_(a) of formula(IIa) and R_(c) of formula (IIc) are R_(ia)NH(═NH)NH—(CH₂)₃— whereinR_(ia) is group —Pbf as already defined;with anhydrous or aqueous organic or inorganic acid to hydrolyze the—Pbf protective groups following procedure well known in the literature.

91b) R_(a)=R_(c) are selected from R_(h)NH(CH₂)_(p)— wherein p is aninteger from 0 to 4, R_(h) is —H:

by reacting a compound of formula (I) with a compound of formula (IIIe)

wherein Y and Y′ are as above defined and A is a radical of formula(IIa), (IIc) or (IIt) wherein R₁ is —H, R₂ is —C(O)OR_(2x) and binds thegroup —Y—ONO₂; R_(a) and R_(c) are R_(h)NH(CH₂)_(p)— wherein p as abovedefined and R_(h) is —C(O)OC(CH₃)₃; d and d′ are as above defined, andR_(t) is —C(O)OC(CH₃)₃; using the same procedure described in 1b′).

91b′) R_(a)=R_(c) selected from R_(i)NH(═NH)NH—(CH₂)₃—, R_(i) is —H:

by reacting a compound of formula (VIIIe) with a compound of formula(IIIe):

wherein Y and Y′ are as above defined and A₇ is a radical of formula(IIa), (IIc) wherein R₁ is —H, R₂ is —C(O)OR_(2x) and binds the group—Y—ONO₂; R_(a) and R_(c) are R_(ia)NH(═NH)NH—(CH₂)₃— wherein R_(ia) isgroup —Pbf as above defined;using the same procedure described in 1b′).

91c) compounds described in 91b) and 91b′) can be respectively preparedby deprotecting the Fmoc group of a compound of formula (VIIIf₁) or(VIIIf₂)

wherein Y is as above defined and:A_(8a) is a radical of formula (IIa), (IIc) or (IIt) wherein R₁ is theFmoc protective group; R₂ is —C(O)OR_(2x) and binds the group —Y—ONO₂;R_(a) and R_(c) are R_(h)NH(CH₂)_(p)— wherein p is as above defined andR_(h) is —C(O)OC(CH₃)₃,A_(8b) is a radical of formula (IIa) or (IIc) wherein R₁ is the Fmocprotective group; R₂ is —C(O)OR_(2x) and binds the group —Y—ONO₂; R_(a)and R_(c) are R_(ia)NH(═NH)NH—(CH₂)₃—, wherein R_(ia) is the —Pbf groupas above defined;

91d) compound of formula (VIIIf₁) or (VIIIf₂) are prepared by reacting acompound of formula A_(9a) or A_(9b) with compound (IIIi) using the sameprocedure described in 8b)

wherein Y is as above defined and:A_(9a) is a radical of formula (IIa), (IIc) or (IIt) wherein R₁ is theFmoc protective group; R₂ is —COOH; R_(a) and R_(c) areR_(h)NH(CH₂)_(p)— wherein p as above defined and R_(h) is —C(O)OC(CH₃)₃;A_(9b) is a radical of formula (IIa) or (IIc) wherein R₁ is the Fmocprotective group; R₂ is —COOH; R_(a) and R_(c) areR_(ia)NH(═NH)NH—(CH₂)₃— wherein R_(ia) is the —Pbf group as previouslydefined.

Compounds A_(9a) and A_(9b) are commercially available.

92. The compounds of general formula (I) wherein:

s and s′ are equal to 1;s″, m, m′ and m″ are equal to 0;Y and Y′ can be equal or different and are as above defined;A is a radical of formula (IIa), (IIc) or (IIt) wherein R₁ is—C(O)—R_(1x) and it binds a group —Y^(f-)ONO₂, R₂ is —C(O)NHR_(2xx) or—C(O)N(CH₃)R_(2xx) and it binds a group —Y—ONO₂;R_(a) of formula (IIa) and R_(c) of formula (IIc) are R_(h)NH(CH₂)_(p)—wherein p is an integer from 0 to 4, or R₂NH(═NH)NH—(CH₂)₃—, and R_(h)and R_(i) are —H;in formula (IIt) R₁ is —C(O)—R_(1x) and binds a group —Y′—ONO₂, R₂ isC(O)NHR_(2xx) or —C(O)N(CH₃)R_(2xx) and it binds a group —Y—ONO₂; d is 2d′ is 1, R_(t) is —H;can be obtained as follows:

92a) R_(a)=R_(c) selected from R_(h)NH(CH₂)_(p)— wherein p is an integerfrom 0 to 4, R_(h) is —H:

by reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″, Y,Y′, Y″ are as above defined in 92. A is a radical of (IIa), (IIc) or(IIt) wherein R₁ is —C(O)—R_(1x); R₂ is —C(O)NHR_(2xx) or—C(O)N(CH₃)R_(2xx);R_(a) of formula (IIa) and R_(c) of formula (IIc) are R_(h)NH(CH₂)_(p)—wherein p is an integer from 0 to 4, R_(h) is —C(O)OC(CH₃)₃;in formula (IIt) R₁ and R₂ are as above defined d is 2 d′ is 1, R_(t) is—C(O)OC(CH₃)₃;with anhydrous or aqueous organic or inorganic acid to hydrolyze the—BOC protective groups following procedure well known in the literature.

92a′) R_(a)=R_(c) selected from R_(i)NH(═NH)NH—(CH₂)₃—, R_(i) is —H:

by reacting a compound of formula (VIIIg)

wherein Y and Y′ are as above defined; A_(10a) is a radical of formula(IIa), (IIc) wherein R₁ R₁ is —C(O)—R_(1x); R₂ is —C(O)NHR_(2xx) or—C(O)N(CH₃)R_(2xx);R_(a) of formula (IIa) and R_(c) of formula (IIc) areR_(ia)—NH(═NH)NH—(CH₂)₃— wherein R_(1a) is the —Pbf groupwith anhydrous or aqueous organic or inorganic acid to hydrolyze the—Pbf protective groups following procedure well known in the literature.

92b) R_(a)=R_(c) are selected from R_(h)NH(CH₂)_(p)— wherein p is aninteger from 0 to 4, R_(h) is —H:

by reacting a compound of formula (I) with a compound of formula

wherein Y and Y′ are as above defined and A is a radical of formula(IIa), (IIc) or (IIt) wherein R₁ is —H, R₂ is —C(O)NHR_(2xx) or—C(O)N(CH₃)R_(2xx) and binds the group —Y—ONO₂; R_(a) and R_(c) areR_(h)NH(CH₂)_(p)— wherein p as above defined and R_(h) is —C(O)OC(CH₃)₃;d and d′ are as above defined, and R_(t) is —C(O)OC(CH₃)₃; using thesame procedure described in 1b′).

92b′) R_(a)=R_(c) selected from R_(i)NH(═NH)NH—(CH₂)₃—, R_(i) is —H:

compound (VIIIg) is prepared by reacting a compound of formula (VIIIh)with a compound of formula (IIIe)

wherein Y and Y′ are as above defined and A is a radical of formula(IIa), (IIc) wherein R₁ is —H, R₂ is —C(O)NHR_(2xx) or—C(O)N(CH₃)R_(2xx) and binds the group —Y—ONO₂; R_(a) and R_(c) areR_(ia)—NH(═NH)NH—(CH₂)₃— wherein R_(ia) is as above definedusing the same procedure described in 1b′).

92c) compounds described in 92b) and 92b′) can be prepared bydeprotecting the Fmoc group of a compound of formula (VIIIi₁) or

wherein Y is as above defined and:A_(11a) is a radical of formula (IIa), (IIc) or (IIt) wherein R₁ is theFmoc protective group; R₂ is —C(O)NHR_(2xx) or —C(O)N(CH₃)R_(2xx) andbinds the group —Y—ONO₂; R_(a) and R_(c) are R_(h)NH(CH₂)_(p)— wherein pis as above defined and R_(h) is —C(O)OC(CH₃)₃,A_(11b) is a radical of formula (IIa) or (IIc) wherein R₁ is the Fmocprotective group; R₂ is —C(O)NHR_(2xx) or —C(O)N(CH₃)R_(2xx) and bindsthe group —Y—ONO₂; R_(a) and R_(c) are R_(ia)NH(═NH)NH—(CH₂)₃—, whereinR_(ia) is as above defined;

92d) compounds described in 92c) can be prepared by reacting a compoundof formula A_(9a) or a compound of formula A_(m) defined in 91d) withcompound (IIIo) using the same procedure described in 7b)

wherein Y and W₃ are as above defined.

93. The compounds of general formula (I) wherein:

s and s′ are equal to 1;s″, m, m′ and m″ are equal to 0;Y and Y′ can be equal or different and are as above defined;A is a radical of formula (IIa), (IIc) and (IIt) wherein R₁ is—C(O)O—R_(1x) and binds a group —Y′—ONO₂, R₂ is —C(O)OR_(2x) and binds agroup —Y—ONO₂;R_(a) of formula (IIa) and R_(c) of formula (IIc) are R_(h)NH(CH₂)_(p)—wherein p is an integer from 0 to 4, or R_(i)NH(═NH)NH—(CH₂)₃—, andR_(h) and R_(i) are —H;in formula (IIt) R₁ is —C(O)O—R_(1x) and binds a group —Y′—ONO₂, and R₂is —C(O)OR_(2x) and binds a group —Y—ONO₂; d is 2 d′ is 1, R_(t) is —H;can be obtained as follows:

93a) R_(a)=R_(c) selected from R_(h)NH(CH₂)_(p)— wherein p is an integerfrom 0 to 4, R_(h) is —H:

by reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″, Y,Y′, Y″ are as above defined in 93. A is a radical of formula (IIa),(IIc) or (IIt) wherein R₁ is —C(O)O—R_(1x); R₂ is —C(O)OR_(2x);R_(a) of formula (IIa) and R_(c) of formula (IIc) are selected fromR_(h)NH(CH₂)_(p)— wherein p is an integer from 0 to 4, R_(h) is—C(O)OC(CH₃)₃;in formula (IIt) R₁ and R₂ are as above defined d is 2 d′ is 1, R_(t) is—C(O)OC(CH₃)₃;with anhydrous or aqueous organic or inorganic acid to hydrolyze the—BOC protective groups following procedure well known in the literature.

93a′) R_(a)=R_(c) selected from R_(i)NH(═NH)NH—(CH₂)₃—, R_(i) is —H:

by reacting a compound of formula (VIIIj)

wherein Y and Y′ are as above defined; A_(11a) is a radical of formula(IIa), (IIc) wherein R₁ is —C(O)O—R_(1x); R₂ is —C(O)OR_(2x) R_(a) offormula (IIa) and R_(c) of formula (IIc) are R_(ia)NH(═NH)NH—(CH₂)₃—wherein R_(ia) is as already defined;with anhydrous or aqueous organic or inorganic acid to hydrolyze the—Pbf protective groups following procedure well known in the literature.

93b) R_(a)=R_(c) are selected from R_(h)NH(CH₂)_(p)— wherein p is aninteger from 0 to 4, R_(h) is —H:

by reacting a compound of formula (I) with a compound of formula (IIIf)

wherein Y and Y′ are as above defined and A is a radical of formula(IIa), (IIc) or (IIt) already defined in 91b) and obtained as describedin 91c), using the same procedure described in 3b).

93b′) R_(a)=R_(c) selected from R_(i)NH(═NH)NH—(CH₂)₃—, R_(i) is —H:

Compound of formula (VIIIj) are prepared by reacting a compound offormula (VIIIe) already defined in 91b′) and obtained as described in91c), with a compound of formula (IIIf)

wherein A₈, Y and Y′ are as above defined, using the same proceduredescribed in 3b).

94. The compounds of general formula (I) wherein:

s and s′ are equal to 1;s″, m, m′ and m″ are equal to 0;Y and Y′ can be equal or different and are as above defined;A is selected from (IIa), (IIc) and (IIt) wherein R₁ is —C(O)O—R_(1x)and binds a group —Y′—ONO₂, R₂ is —C(O)NHR_(2xx) or —C(O)N(CH₃)R_(2xx)and binds a group —Y—ONO₂;R_(a) of formula (IIa) and R_(c) of formula (IIc) are R_(h)NH(CH₂)_(p)—wherein p is an integer from 0 to 4, or R₂NH(═NH)NH—(CH₂)₃—, and R_(h)and R_(i) are —H;in formula (IIt) R₁ is —C(O)O—R_(1x) and binds a group —Y′—ONO₂, and R₂is —C(O)NHR_(2xx) or —C(O)N(CH₃)R_(2xx) and binds a group —Y—ONO₂; d is2 d′ is 1, R_(t) is —H;can be obtained as follows:

94a) R_(a)=R_(c) selected from R_(h)NH(CH₂)_(p)— wherein p is an integerfrom 0 to 4, R_(h) is —H;

by reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″, Y,Y′, Y″ are as above defined in 94. A is a radical of (IIa), (IIc) or(IIt) wherein R₈ is —C(O)O—R_(1x); R₂ is —C(O)NHR_(2xx) or—C(O)N(CH₃)R_(2xx);R_(a) of formula (IIa) and R_(c) of formula (IIc) are selected fromR_(h)NH(CH₂)_(p)— wherein p is an integer from 0 to 4, R_(h) is—C(O)OC(CH₃)₃;in formula (IIt) R₁ and R₂ are as above defined d is 2 d′ is 1, R_(t) is—C(O)OC(CH₃)₃;with anhydrous or aqueous organic or inorganic acid to hydrolyze the—BOC protective groups following procedure well known in the literature.

94a′) R_(a)=R_(c) selected from R_(i)NH(═NH)NH—(CH₂)₃—, R_(i) is —H:

by reacting a compound of formula (VIIIk)

wherein Y and Y′ are as above defined; A_(12a) is a radical of formula(IIa), (IIc) wherein R₁ is —C(O)O—R_(1x); R₂ is —C(O)NHR_(2xx) or—C(O)N(CH₃)R_(2xx);R_(a) of formula (IIa) and R_(c) of formula (IIc) are R_(ia)NH(═NH)NH(CH₂)₃— wherein R_(ia) is group —Pbfwith anhydrous or aqueous organic or inorganic acid to hydrolyze the—Pbf protective groups following procedure well known in the literature.

94b) R_(a)=R_(c) are selected from R_(h)NH(CH₂)_(p)— wherein p is aninteger from 0 to 4, R_(h) is —H:

by reacting a compound of formula (I) with a compound of formula (IIIf)

wherein Y and Y′ are as above defined and A is a radical of formula(IIa), (IIc) or (IIt) already defined in 92b) and obtained as describedin 92c), using the same procedure described in 3b).

94b′) R_(a)=R_(c) selected from R_(i)NH(═NH)NH—(CH₂)₃—, R_(i) is —H:

Compound (VIIIk) are prepared by reacting a compound of formula (VIIIk)already defined in 92b′) and obtained as described in 92c), with acompound of formula (IIIf)

wherein Y and Y′ are as above defined using the same procedure describedin 3b).

95. The compounds of general formula (I) wherein:

s, s′ and s″ are equal to 1;m, m′ and m″ are equal to 0;Y, Y′ and Y″ are as above defined, with the proviso that Y and Y′ areequal;A is selected from (IIa), (IIc) and (IIt) wherein R₁ is —C(O)—R_(1x) andit binds a group —Y—ONO₂ or a group —Y′—ONO₂, R₂ is —C(O)OR_(2x) and itbinds a group —Y″—ONO₂;R_(a) of formula (IIa) and R_(c) of formula (IIc) are R_(h)NH(CH₂)_(p)—wherein p is an integer from 0 to 4, or R_(i)NH(═NH)NH—(CH₂)₃—, whereinR_(h) and R_(i) are R_(hh)—C(O)— or R_(ii)—C(O) and R_(a) and R_(c) binda group —Y—ONO₂ or a group —Y′—ONO₂;in formula (IIt) R₁ and R₂ are as above defined, d is 2 d′ is 1, R_(t)is —C(O)—R_(tt) and it binds a group —Y—ONO₂ or a group —Y′—ONO₂;can be prepared as follows:

95a) by reacting a compound of formula (I) with a compound of formula(IIIi)

wherein in compounds (I), obtained as described in 86. Y and Y′ areequal and are as above defined and A is selected from (IIa), (IIc) and(IIt) wherein R₁ is —C(O)—R_(1x) and binds a group —Y—ONO₂ or a group—Y′—ONO₂ and R₂ is —COOH;R_(a) of formula (IIa) and R_(c) of formula (IIc) are R_(h)NH(CH₂)_(p)—wherein p is an integer from 0 to 4, or R_(i)NH(═NH)NH—(CH₂)₃—, andR_(h) and R_(i) are R_(hh)—C(O)— or R_(aa)—C(O)— and bind a group—Y—ONO₂ or a group —Y′—ONO₂;in formula (IIt) R₁ and R₂ are as above defined, d is 2 d′ is 1, R_(t)is —C(O)—R_(tt) and it binds a group —Y—ONO₂ or a group —Y′—ONO₂; usingthe same procedure described in 8b).

96. The compounds of general formula (I) wherein:

s, s′ and s″ are equal to 1;m, m′ and m″ are equal to 0;Y, Y′ and Y″ are as above defined, with the proviso that Y and Y′ areequal;A is a radical of formula (IIa), (IIc) and (IIt) wherein R₁ is—C(O)O—R_(1x) and it binds a group —Y—ONO₂ or a group —Y′—ONO₂, R₂ is—C(O)OR_(2x) and it binds a group —Y″—ONO₂;R_(a) of formula (IIa) and R_(c) of formula (IIc) are R_(h)NH(CH₂)_(p)—wherein p is an integer from 0 to 4, or R_(i)NH(═NH)NH—(CH₂)₃—, whereinR_(h) and R_(i) are R_(hh)—OC(O) or R_(ii)—OC(O)— and R_(a) and R_(c)bind a group —Y—ONO₂ or a group —Y′—ONO₂;in formula (IIt) R₁ and R₂ are as above defined, d is 2 d′ is 1, R_(t)is —C(O)O—R_(tt) and binds a group —Y—ONO₂ or a group —Y′—ONO₂;can be prepared as follows:

96a) by reacting a compound of formula (I) with a compound of formula(IIIi)

wherein in compounds (I), obtained as described in 87. Y and Y′ areequal and are as above defined and A is selected from (IIa), (IIc) and(IIt) wherein R₁ is —C(O)O—R_(1x) and binds a group —Y—ONO₂ or a group—Y′—ONO₂ and R₂ is —COOH;R_(a) of formula (IIa) and R_(c) of formula (IIc) are R_(h)NH(CH₂)_(p)—wherein p is an integer from 0 to 4, or R_(i)NH(═NH)NH—(CH₂)₃—, andR_(h) and R_(i) are R_(hh)—OC(O)— or R_(ii)—OC(O) and bind a group—Y—ONO₂ or a group —Y′—ONO₂;in formula (IIt) R₁ and R₂ are as above defined, d is 2 d′ is 1, R_(t)is —C(O)O—R_(tt) and binds a group —Y—ONO₂ or a group —Y′—ONO₂; usingthe same procedure described in 8b).

97. The compounds of general formula (I) wherein:

s, s′ and s″ are equal to 1;m, m′ and m″ are equal to 0;Y, Y′ and Y″ are as above defined, and Y and Y′ are equal;

A is a radical of formula from (IIa), (IIc) or (IIt) wherein R₁ is—C(O)—R_(1x) and it binds a group —Y—ONO₂ or a group —Y′—ONO₂, R₂ is—C(O)NHR_(2xx) or —C(O)N(CH₃)R_(2xx) and it binds a group —Y″—ONO₂;

R_(a) of formula (IIa) and R_(c) of formula (IIc) are R_(h)NH(CH₂)_(p)—wherein p is an integer from 0 to 4, or R_(i)NH(═NH)NH—(CH₂)₃—, whereinR_(h) and R_(i) are R_(hh)—C(O)— or R_(ii)—C(O)— and R_(a) and R_(c)bind a group —Y—ONO₂ or a group —Y′—ONO₂;in formula (IIt) R₁ and R₂ are as above defined, d is 2 d′ is 1, R_(t)is —C(O)—R_(tt) and binds a group —Y—ONO₂ or a group —Y′—ONO₂;can be prepared as follows:

97a) by reacting a compound of formula (I) with a compound of formula(IIIo)

wherein in compounds (I), obtained as described in 86. Y and Y′ areequal and are as above defined and A is selected from (IIa), (IIc) and(IIt) wherein R₁ is —C(O)—R_(1x) and binds a group —Y—ONO₂ or a group—Y′—ONO₂ and R₂ is —COOH;R_(a) of formula (IIa) and R_(c) of formula (IIc) are R_(h)NH(CH₂)_(p)—wherein p is an integer from 0 to 4, or R_(i)NH(═NH)NH—(CH₂)₃—, andR_(h) and R_(i) are R_(hh)—C(O)— or R_(ii)—C(O)— and bind a group—Y—ONO₂ or a group —Y′—ONO₂;in formula (IIt) R₁ and R₂ are as above defined, d is 2 d′ is 1, R_(t)is —C(O)—R_(tt) and binds a group —Y—ONO₂ or a group —Y′—ONO₂;using the same procedure described in 7b).

98. The compounds of general formula (I) wherein:

s, s′ and s″ are equal to 1;m, m′ and m″ are equal to 0;Y, Y′ and Y″ are as above defined and Y and Y′ are equal;A is selected from (IIa), (IIc) and (IIt) wherein R₁ is —C(O)O —R_(1x)and binds a group —Y—ONO₂ or a group —Y′—ONO₂, R₂ is —C(O)NHR_(2xx) or—C(O)N(CH₃)R_(2xx) and binds a group —Y″—ONO₂;R_(a) of formula (IIa) and R_(c) of formula (IIc) are R_(h)NH(CH₂)_(p)—wherein p is an integer from 0 to 4, or R_(i)NH(═NH)NH—(CH₂)₃—, whereinR_(h) and R_(i) are R_(hh)—OC(O)— or R_(ii)—OC(O)— and R_(a) and R_(c)bind a group —Y—ONO₂ or a group —Y′—ONO₂;in formula (IIt) R₁ and R₂ are as above defined, d is 2 d′ is 1, R_(t)is —C(O)O—R_(tt) and binds a group —Y—ONO₂ or a group —Y′—ONO₂;can be prepared as follows:

98a) by reacting a compound of formula (I) with a compound of formula(IIIo)

wherein in compounds (I), obtained as described in 87. Y and Y′ areequal and are as above defined, W₃ is as above defined and A is selectedfrom (IIa), (IIc) and (IIt) wherein R₁ is —C(O)O—R_(1x) and binds agroup —Y—ONO₂ or a group —Y′—ONO₂ and R₂ is —COOH;R_(a) of formula (IIa) and R_(c) of formula (IIc) are R_(h)NH(CH₂)_(p)—wherein p is an integer from 0 to 4, or R_(i)NH(═NH)NH—(CH₂)₃—, andR_(h) and R_(i) are R_(hh)—OC(O)— or R_(ii)—OC(O)— and bind a group—Y—ONO₂ or a group —Y′—ONO₂;in formula (IIt) R₁ and R₂ are as above defined, d is 2 d′ is 1, R_(t)is —C(O)O—R_(tt) and binds a group —Y—ONO₂ or a group —Y′—ONO₂;using the same procedure described in 7b).

99. The compounds of general formula (I) wherein:

s, s′, s″ and m″ are equal to 1;m, m′ are equal to 0;Y, Y′ and Y″ are as above defined, with the proviso that Y andY′ are equal;

B is:

A is a radical of formula (IIa), (IIc) or (IIt) wherein R₁ is —C(O) andbinds a group —Y—ONO₂ or a group —Y′—ONO₂, R₂ is —C(O)OR_(2x) and bindsa group —B—Y″—ONO₂;R_(a) of formula (IIa) and R_(c) of formula (IIc) are R_(h)NH(CH₂)_(p)—wherein p is an integer from 0 to 4, or R_(i)NH(═NH)NH—(CH₂)₃—, whereinR_(h) and R_(i) are R_(hh)—C(O)— or R_(ii)—C(O)— and R_(a) and R_(c)bind a group —Y—ONO₂ or a group —Y′—ONO₂;in formula (IIt) R₁ and R₂ are as above defined, d is 2 d′ is 1, R_(t)is —C(O)—R_(tt) and binds a group —Y—ONO₂ or a group —Y′—ONO₂;can be prepared as follows:

99a) by reacting a compound of formula (I) obtained as described in 86.

with compounds (IIIg) or (IIIn) depending on the meaning of B:

(I)+Hal-W₁—OC(O)O—Y′—ONO₂  (IIIg)

(I)+Hal-W₁—OC(O)—Y′—ONO₂  (IIIn)

wherein in compounds (I), obtained as described in 86. Y and Y′ areequal and are as above defined and A is selected from (IIa), (IIc) and(IIt) wherein R₁ is —C(O)R_(1x) and binds a group —Y—ONO₂ or a group—Y′—ONO₂ and R₂ is —COOH;R_(a) of formula (IIa) and R_(c) of formula (IIc) are R_(h)NH(CH₂)_(p)—wherein p is an integer from 0 to 4, or R_(i)NH(═NH)NH—(CH₂)₃—, andR_(h) and R_(i) are R_(hh)—C(O)— or R_(ii)—C(O) and bind a group —Y—ONO₂or a group —Y′—ONO₂;in formula (IIt) R₁ and R₂ are as above defined, d is 2 d′ is 1, R_(t)is —C(O)—R_(tt) and binds a group —Y—ONO₂ or a group —Y′—ONO₂; andapplying the same procedure described in 4b) or 6b).

100. The compounds of general formula (I) wherein:

s, s′, s″ and m″ are equal to 1;m, m′ are equal to 0;Y, Y′ and Y″ are as above defined, with the proviso that Y andY′ are equal;

B is:

A is a radical of formula (IIa), (IIc) and (IIt) wherein R₁ is—C(O)O—R_(1x) and it binds a group —Y—ONO₂ or a group —Y′—ONO₂, R₂ is—C(O)OR_(2x) and it binds a group —B—Y″—ONO₂;R_(a) of formula (IIa) and R_(c) of formula (IIc) are R_(h)NH(CH₂)_(p)—wherein p is an integer from 0 to 4, or R_(i)NH(═NH)NH—(CH₂)₃—, whereinR_(h) and R_(i) are R_(hh)—OC(O) or R_(ii)—OC(O)— and R_(a) and R_(c)bind a group —Y—ONO₂ or a group —Y′—ONO₂;in formula (IIt) R₁ and R₂ are as above defined, d is 2 d′ is 1, R_(t)is —C(O)O—R_(tt) and it binds a group —Y—ONO₂ or a group —Y′—ONO₂; canbe prepared as follows:

100a) by reacting a compound of formula (I) obtained as described in 87.

with compounds (IIIg) or (IIIn) depending on the meaning of B:

(I)+Hal-W₁—OC(O)O—Y′—ONO₂  (IIIg)

(I)+Hal-W₁—OC(O)—Y′—ONO₂

wherein in compounds (I) Y and Y′ are equal and are as above defined andA is selected from (IIa), (IIc) and (IIt) wherein R₁ is —C(O)O—R_(1x)and binds a group —Y—ONO₂ or a group —Y′—ONO₂ and R₂ is —COOH;R_(a) of formula (IIa) and R_(c) of formula (IIc) are R_(h)NH(CH₂)_(p)—wherein p is an integer from 0 to 4, or R_(i)NH(═NH)NH—(CH₂)₃—, andR_(h) and R_(i) are R_(hh)—C(O)— or R_(ii)—C(O)— and bind a group—Y—ONO₂ or a group —Y′—ONO₂;in formula (IIt) R₁ and R₂ are as above defined, d is 2 d′ is 1, R_(t)is —C(O)O—R_(tt) and binds a group —Y—ONO₂ or a group —Y′—ONO₂; andapplying the same procedure described in 4b) or 6b).

101. The compounds of general formula (I) wherein:

s and s′ are equal to 1;s″, m, m′ and m″ are equal to 0;Y and Y′ can be equal or different and are as above defined;A is a radical of formula (IIa), (IIc) or (IIt) wherein R₁ is —H, R₂ is—C(O)OR_(2x) and it binds a group —Y—ONO₂;R_(a) of formula (IIa) and R_(c) of formula (IIc) are R_(h)NH(CH₂)_(p)—wherein p is an integer from 0 to 4, or R_(i)NH(═NH)NH—(CH₂)₃—, whereinR_(h) and R_(i) are R_(hh)—C(O)— or R_(ii)—C(O)— and R_(a) and R_(c)bind a group —Y′—ONO₂in formula (IIt) R₁ is —H, and R₂ is —C(O)OR_(2x) and binds a group—Y—ONO₂; d is 2 d′ is 1, R_(t) is —C(O)—R_(tt), and binds a group—Y′—ONO₂can be obtained as follows:

101a) R_(a)=R_(c) selected from R_(h)NH(CH₂)_(p)— wherein p is aninteger from 0 to 4, R_(h) is R_(hh)—C(O)—;

by reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″, Y,Y′, Y″ are as above defined in 101, A is a radical of (IIa), (IIc) or(IIt) wherein R₂, d, d′, R_(t) are as defined in 101, R_(a) and R_(c)are selected from R_(h)NH(CH₂)_(p)— wherein p is an integer from 0 to 4,R_(h) is R_(hh)—C(O)—; R₁ is —C(O)OC(CH₃)₃;with anhydrous or aqueous organic or inorganic acid to hydrolyze the—BOC protective groups following procedure well known in the literature.

101a′) R_(a)=R_(c) selected from R_(i)NH(═NH)NH—(CH₂)₃—, R_(i) isR_(ii)—C(O)—;

by reacting a compound of formula (VIIIL)

wherein Y and Y′ are as above defined; A_(13a) is a radical of formula(IIa), (IIc) wherein R₁ is the -Fmoc protective group; R₂ is—C(O)OR_(2x) and binds a group —Y—ONO₂; R_(a) of formula (IIa) and R_(c)of formula (IIc) are R_(i)NH(═NH)NH—(CH₂)₃— wherein R_(i) isR_(ii)—C(O)— and binds a group —Y′—ONO₂ by known procedure to remove the-Fmoc protective groups;

101b) R_(a)=R_(c) are selected from R_(h)NH(CH₂)_(p)— wherein p is aninteger from 0 to 4, R_(h) is —H:

by reacting a compound of formula (I) with a compound of formula (IIIe)

wherein Y and Y′ are as above defined and A is a radical of formula(IIa), (IIc) or (IIt) wherein R₁ is —C(O)OC(CH₃)₃; —R₂ is —C(O)OR_(2x)and binds the group —Y—ONO₂; R_(a) and R_(c) are selected fromR_(h)NH(CH₂)_(p)— wherein p as above defined and R_(h) is —H; in formula(IIt) d and d′ are as above defined, and R_(t) is —H;using the same procedure described in 1b′).

101b′) R_(a)=R_(c) selected from R_(i)NH(═NH)NH—(CH₂)₃—, R_(i) is —H:

Compound (VIIIL) are prepared by reacting a compound of formula (VIIIm)with a compound of formula (IIIe)

wherein Y and Y′ are as above defined and A₁₃ is a radical of formula(IIa), (IIc) wherein R₁ is the Fmoc protective group, R₂ is —C(O)OR_(2x)and binds the group —Y—ONO₂; R_(a) and R_(c) are R_(i)NH(═NH)NH—(CH₂)₃—wherein R_(i) is —H using the same procedure described in 1b′).

101c) R_(a)=R_(c) are selected from R_(ha)NH(CH₂)_(p)— wherein p is aninteger from 0 to 4, R_(ha) is -Fmoc:

by deprotecting the Fmoc group of a compound of formula (VIIIn)

wherein Y is as above defined and A₁₄ is a radical of formula (IIa),(IIc) or (IIt) wherein R₁ is —C(O)OC(CH₃)₃; R₂ is —C(O)OR_(2x) and bindsthe group —Y—ONO₂; R_(a) and R_(c) are R_(ha)NH(CH₂)_(p)— wherein p asabove defined and R_(ha) is the Fmoc protective group; d and d′ are asabove defined, and R_(t) is equal to R_(ta) and is the Fmoc protectivegroup

101′c) R_(a)=R_(c) selected from R_(ia)NH(═NH)NH—(CH₂)₃—, R_(ia)=—Pbf

Compound (VIIIm) are prepared by deprotecting the —Pbf group of acompound of formula (VIIIo)

wherein Y is as above defined and A_(15a) is a radical of formula (IIa),(IIc) wherein R₁ is -Fmoc; R₂ is —C(O)OR_(2x) and binds the group—Y—ONO₂; R_(a) and R_(c) are R_(ia)NH(═NH)NH—(CH₂)₃—R_(ia) is the —Pbfprotective group;

101d) compound described in 101c) and 101c′) can be prepared by reactinga compound of formula A₁₄ or A₁₅ with compound (IIIi) using the sameprocedure described in 8b)

wherein Y is as above defined and:A₁₄ is a radical of formula (IIa), (IIc) or (IIt) wherein R₁ is—C(O)OC(CH₃)₃; R₂ is —COOH; R_(a) and R_(c) are R_(ha)NH(CH₂)_(p)—wherein p as above defined and R_(ha) is the Fmoc protective group; dand d′ are as above defined, and R_(t) is R_(ta) and is the Fmocprotective group. A₁₅ is a radical of formula (IIa), (IIc) wherein R₁ is-Fmoc; R₂ is —COOH; R_(a) and R_(c) are selected fromR_(ia)NH(═NH)NH—(CH₂)₃—, wherein R_(ia) is —Pbf.

Compounds A₁₄ and A₁₅ are commercially available.

102. The compounds of general formula (I) wherein:

s and s′ are equal to 1;s″, m, m′ and m″ are equal to 0;Y and Y′ can be equal or different and are as above defined;A is selected from (IIa), (IIc) and (IIt) wherein R₁ is —H, R₂ is—C(O)OR_(2x) and binds a group —Y—ONO₂;R_(a) of formula (IIa) and R_(c) of formula (IIc) are R_(h)NH(CH₂)_(p)—wherein p is an integer from 0 to 4, or R_(i)NH(═NH)NH—(CH₂)₃—, whereinR_(h) and R_(i) are R_(hh)—OC(O)— or R_(ii)—OC(O) and binds a group—Y′—ONO₂in formula (IIt) R₁ is —H, and R₂ is —C(O)OR_(2x) and binds a group—Y—ONO₂; d is 2 d′ is 1, R_(t) is —C(O)O—R_(tt), and binds a group—Y′—ONO₂can be obtained as follows:

102a) R_(a)=R_(c) selected from R_(h)NH(CH₂)_(p)— wherein p is aninteger from 0 to 4, R_(h) is R_(hh)—OC(O)—:

by reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″, Y,Y′, Y″ are as above defined in 102, A is a radical of (IIa), (IIc) or(IIt) wherein R₂, d, d′, R_(t) are as defined in 102, R_(a) and R_(c)are selected from R_(h)NH(CH₂)_(p)— wherein p is an integer from 0 to 4,R_(h) is R_(hh)—OC(O)—; R₁ is —C(O)OC(CH₃)₃;with anhydrous or aqueous organic or inorganic acid to hydrolyze the—BOC protective groups following procedure well known in the literature.

102a′) R_(a)=R_(c) selected from R_(i)NH(═NH)NH—(CH₂)₃—, R_(i) isR_(ii)—OC(O)—;

by reacting a compound of formula (VIIIA)

wherein Y and Y′ are as above defined; A₁₆ is a radical of formula(IIa), (IIc) wherein R₁ is the -Fmoc protective group; R₂ is—C(O)OR_(2x) and binds a group —Y—ONO₂; R_(a) of formula (IIa) and R_(c)of formula (IIc) are R_(i)NH(═NH)NH—(CH₂)₃— wherein R_(i) isR_(ii)—OC(O)— and binds a group —Y′—ONO₂ by known procedure to removethe -Fmoc protective groups;

102b) R_(a)=R_(c) are selected from R_(h)NH(CH₂)_(p)— wherein p is aninteger from 0 to 4, R_(h) is —H:

by reacting a compound of formula (I) with a compound of formula (IIIf)

wherein Y and Y′ are as above defined and A is as above defined in101b), using the same procedure described in 3b).

102b′) R_(a)=R_(c) selected from R_(i)NH(═NH)NH—(CH₂)₃—, R_(i) is —H:

by reacting a compound of formula (VIIIm) already described in 101b′)and obtained as described in 101c′) with a compound of formula (IIIf)

wherein Y and Y′ are as above defined and A_(13′) is as defined in101b′) using the same procedure described in 3b).

103. The compounds of general formula (I) wherein:

s and s′ are equal to 1;s″, m, m′ and m″ are equal to 0;Y and Y′ can be equal or different and are as above defined;A is selected from (IIa), (IIc) and (IIt) wherein R₁ is —H, R₂ is—C(O)NHR_(2xx) or —C(O)N(CH₃)R_(2xx) and binds a group —Y—ONO₂;R_(a) of formula (IIa) and R_(c) of formula (IIc) are R_(h)NH(CH₂)_(p)—wherein p is an integer from 0 to 4, or R_(i)NH(═NH)NH—(CH₂)₃—, whereinR_(h) and R_(i) are R_(hh)—C(O)— or R_(ii)—C(O)—, and binds a group—Y′—ONO₂in formula (IIt) R₁ is —H, and R₂ is —C(O)NHR_(2xx) or—C(O)N(CH₃)R_(2xx) and binds a group —Y—ONO₂; d is 2 d′ is 1, R_(t) is—C(O)—R_(tt), and binds a group —Y′—ONO₂can be obtained as follows:

103a) R_(a)=R_(c) selected from R_(h)NH(CH₂)_(p)— wherein p is aninteger from 0 to 4, R_(h) is R_(hh)—C(O):

by reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″, Y,Y′, Y″ are as above defined in 103, A is a radical of (IIa), (IIc) or(IIt) wherein R₂, d, d′, R_(t) are as defined in 103, R_(a) and R_(c)are selected from R_(h)NH(CH₂)_(p)— wherein p is an integer from 0 to 4,R_(h) is R_(hh)—C(O)—; R₁ is —C(O)OC(CH₃)₃;with anhydrous or aqueous organic or inorganic acid to hydrolyze the—BOC protective groups following procedure well known in the literature.

103a) R_(a)=R_(c) selected from R_(i)NH(═NH)NH—(CH₂)₃—, R_(i) isR_(ii)—C(O)—;

by reacting a compound of formula (VIIIq)

wherein Y and Y′ are as above defined; A_(17a) is a radical of formula(IIa), (IIc) wherein R₁ is the -Fmoc protective group; R₂ is—C(O)NHR_(2xx) or —C(O)N(CH₃)R_(2xx) and binds a group —Y—ONO₂; R_(a) offormula (IIa) and R_(c) of formula (IIc) are R_(i)NH(═NH)NH—(CH₂)₃—wherein R_(i) is R_(ii)—C(O)— and binds a group —Y′—ONO₂ by knownprocedure to remove the -Fmoc protective groups;

103b) R_(a)=R_(c) are selected from R_(h)NH(CH₂)_(p)— wherein p is aninteger from 0 to 4, R_(h) is —H

by reacting a compound of formula (I) with a compound of formula (IIIe)

wherein Y and Y′ are as above defined and A is a radical of formula(IIa), (IIc) or (IIt) wherein R₁ is —C(O)OC(CH₃)₃; —R₂ is —C(O)NHR_(2xx)or —C(O)N(CH₃)R_(2xx) and binds the group —Y—ONO₂; R_(a) and R_(c) areR_(h)NH(CH₂)_(p)— wherein p as above defined and R_(h) is —H; in formula(IIt) d and d′ are as above defined, and R_(t) is —H;using the same procedure described in 1b′).

103b′) R_(a)=R_(c) selected from R_(i)NH(═NH)NH—(CH₂)₃—, R_(i) is —H:

by reacting a compound of formula (VIIIr) with a compound of formula(IIIe)

wherein Y and Y′ are as above defined and A₁₇ is a radical of formula(IIa), (IIc) wherein R₁ is the Fmoc protective group, R₂ is—C(O)NHR_(2xx) or —C(O)N(CH₃)R_(2xx) and binds the group —Y—ONO₂; R_(a)and R_(c) are R_(i)NH(═NH)NH—(CH₂)₃— wherein R_(i) is —H using the sameprocedure described in 1b′).

103c) R_(a)=R_(c) are selected from R_(ha)NH(CH₂)_(p)— wherein p is aninteger from 0 to 4, R_(ha) is -Fmoc

Compound (I) described in 103b) can be prepared by deprotecting the Fmocgroup of a compound of formula (VIIIs)

wherein Y is as above defined and A₁₈ is a radical of formula (IIa),(IIc) or (IIt) wherein R₁ is —C(O)OC(CH₃)₃; R₂ is —C(O)NHR_(2xx) or—C(O)N(CH₃)R_(2xx) and binds the group —Y—ONO₂; R_(a) and R_(c) areR_(ha)NH(CH₂)_(p)— wherein p as above defined and R_(ha) is the Fmocprotective group; d and d′ are as above defined, and R_(t) is R_(ta) andis the Fmoc group.

103c′) R_(a)=R_(c) selected from R_(ia)NH(═NH)NH—(CH₂)₃—, R_(ia)=—Pbf

Compound (VIIIr) described in 103b′) by deprotecting the —Pbf group of acompound of formula (VIIIt)

wherein Y is as above defined and A₁₉ is a radical of formula (IIa),(IIc) wherein R₁ is -Fmoc; R₂ is —C(O)NHR_(2xx) or —C(O)N(CH₃)R_(2xx)and binds the group —Y—ONO₂; R_(a) and R_(c) areR_(ia)NH(═NH)NH—(CH₂)₃—R_(ia) is the —Pbf protective group;

103d) compounds described in 103c) and 103c′) can be prepared byreacting a compound of formula A₁₄ or A₁₅ described in 101d) withcompound (IIIo) using the same procedure described in 7b)

wherein Y is as above defined and W₃ is H or —CH₃.

104. The compounds of general formula (I) wherein:

s and s′ are equal to 1;s″, m, m′ and m″ are equal to 0;Y and Y′ can be equal or different and are as above defined;A is selected from (IIa), (IIc) and (IIt) wherein R₁ is —H, R₂ is—C(O)NHR_(2xx) or —C(O)N(CH₃)R_(2xx) and binds a group —Y—ONO₂;R_(a) of formula (IIa) and R_(c) of formula (IIc) are R_(h)NH(CH₂)_(p)—wherein p is an integer from 0 to 4, or R_(i)NH(═NH)NH—(CH₂)₃—,wherein R_(h) and R_(i) are R_(hh)—OC(O)— or R_(ii)—OC(O)—, and binds agroup —Y′—ONO₂;in formula (IIt) R₁ is —H, and R₂ is —C(O)NHR_(2xx) or—C(O)N(CH₃)R_(2xx) and binds a group —Y—ONO₂; d is 2 d′ is 1, R_(t) is—C(O)O—R_(xx), and binds a group —Y′—ONO₂can be obtained as follows:

104a) R_(a)=R_(c) selected from R_(h)NH(CH₂)_(p)— wherein p is aninteger from 0 to 4, R_(h) is

by reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″, Y,Y′, Y″ are as above defined in 104, A is a radical of (IIa), (IIc) or(IIt) wherein R₂, d, d′, R_(t) are as defined in 104, R_(a) and R_(c)are selected from R_(h)NH(CH₂)_(p)— wherein p is an integer from 0 to 4,R_(h) is R_(hh)—O—C(O)—; R₁ is —C(O)OC(CH₃)₃;with anhydrous or aqueous organic or inorganic acid to hydrolyze the—BOC protective groups following procedure well known in the literature.

104a′) R_(a)=R_(c) selected from R_(i)NH(═NH)NH—(CH₂)₃—, R_(i) isR_(ii)—OC(O)—;

by reacting a compound of formula (VIIIu)

wherein Y and Y′ are as above defined and A₂₀ is a radical of formula(IIa), (IIc) wherein R₁ is the -Fmoc protective group; R₂ is—C(O)NHR_(2xx) or —C(O)N(CH₃)R_(2xx) and binds a group —Y—ONO₂; R_(a) offormula (IIa) and R_(c) of formula (IIc) are R_(i)NH(═NH)NH—(CH₂)₃—wherein R_(i) is R_(ii)—OC(O)— and binds a group —Y′—ONO₂ by knownprocedure to remove the -Fmoc protective groups;

104b) R_(a)=R_(c) are selected from R_(h)NH(CH₂)_(p)— wherein p is aninteger from 0 to 4, R_(h) is —H

by reacting a compound of formula (I) with a compound of formula (IIIf)

wherein Y and Y′ are as above defined and A is as defined in 103b),using the same procedure described in 3b).

104b′) R_(a)=R_(c) selected from R_(i)NH(═NH)NH—(CH₂)₃—, R_(i) is —H:

Compound (VIIIu) can be prepared by reacting a compound of formula(VIIIr) with a compound of formula (IIIf)

wherein Y and Y′ are as above defined and A₁₇ is as defined in 103b′)using the same procedure described in 3b).

105. The compounds of general formula (I) wherein:

s, s′ and m are equal to 1;s″, m′ and m″ are equal to 0;Y and Y′ are as above defined;

B is:

A is selected from (IIa), (IIc) and (IIt) wherein R₁ is —H, R₂ is—C(O)OR_(2x) and binds a group —B—Y—ONO₂;R_(a) of formula (IIa) and R_(c) of formula (IIc) are R_(h)NH(CH₂)_(p)—wherein p is an integer from 0 to 4, or R_(i)NH(═NH)NH—(CH₂)₃—, whereinR_(h) and R_(i) are R_(hh)—C(O)— or R_(ii)—C(O)—, and bind a group—Y′—ONO₂in formula (IIt) R₁ is —H, and R₂ is —C(O)OR_(2x) and binds a group—B—Y—ONO₂, d is 2 d′ is 1, R_(t) is —C(O)—R_(tt) and binds a group—Y′—ONO₂;can be obtained as follows:

105a) R_(a)=R_(c) selected from R_(h)NH(CH₂)_(p)— wherein p is aninteger from 0 to 4, R_(h) is R_(hh)—C(O)—:

by reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″, B,Y, Y′, Y″ are as above defined in 105, A is a radical of (IIa), (IIc) or(IIt) wherein R₂, d, d′, R_(t) are as defined in 105, R_(a) and R_(c)are selected from R_(h)NH(CH₂)_(p)— wherein p is an integer from 0 to 4,R_(h) is R_(hh)—C(O)—; R₁ is —C(O)OC(CH₃)₃;with anhydrous or aqueous organic or inorganic acid to hydrolyze the—BOC protective groups following procedure well known in the literature.

105a′) R_(a)=R_(c) selected from R_(i)NH(═NH)NH—(CH₂)₃—, R_(i) isR_(ii)—C(O)—;

by reacting a compound of formula (VIIIv)

wherein B, Y and Y′ are as above defined and A_(21a) is a radical offormula (IIa), (IIc) wherein R₁ is the -Fmoc protective group; R₂ is—C(O)OR_(2x) and binds a group —B—Y—ONO₂; R_(a) of formula (IIa) andR_(c) of formula (IIc) are R_(i)NH(═NH)NH—(CH₂)₃— wherein R_(i) isR_(ii)—C(O)— and binds a group —Y′—ONO₂ by known procedure to remove the-Fmoc protective groups;

105b) R_(a)=R_(c) are selected from R_(h)NH(CH₂)_(p)— wherein p is aninteger from 0 to 4, R_(h) is —H

by reacting a compound of formula (I) with a compound of formula (IIIe)

wherein Y and Y′ are as above defined and A is a radical of formula(IIa), (IIc) or (IIt) wherein R₁ is —C(O)OC(CH₃)₃; —R₂ is —C(O)OR_(2x)and binds the group —B—Y—ONO₂; R_(a) and R_(c) are R_(h)NH(CH₂)_(p)—wherein p as above defined and R_(h) is —H; in formula (IIt) d and d′are as above defined, and R_(t) is —H;using the same procedure described in 1b′);

105b′) R_(a)=R_(c) selected from R_(i)NH(═NH)NH—(CH₂)₃—, R_(i) is —H:

Compound of formula (VIIIv) can be prepared by reacting a compound offormula (VIIIw) with a compound of formula (IIIe)

wherein Y and Y′ are as above defined and A₂₁ is a radical of formula(IIa), (IIc) wherein R₁ is the Fmoc protective group, R₂ is —C(O)OR_(2x)and binds the group —B—Y—ONO₂; R_(a) and R_(c) areR_(i)NH(═NH)NH—(CH₂)₃— wherein R_(i) is —H using the same proceduredescribed in 1b′).

105c) R_(a)=R_(c) are selected from R_(ha)NH(CH₂)_(p)— wherein p is aninteger from 0 to 4, R_(ha) is -Fmoc

Compound (I) described in 105b) by deprotecting the Fmoc group of acompound of formula (VIIIx)

wherein Y and B are as above defined and A₂₂ is a radical of formula(IIa), (IIc) or (IIt) wherein R₁ is —C(O)OC(CH₃)₃; R₂ is —C(O)OR_(2x)and binds the group —B—Y—ONO₂; R_(a) and R_(c) are R_(ha)NH(CH₂)_(p)—wherein p as above defined and R_(ha) is the Fmoc protective group; dand d′ are as above defined, and R_(t) is R_(ta) and is the Fmocprotecting group.

105c′) R_(a)=R_(c) selected from R_(ia)NH(═NH)NH—(CH₂)₃, R_(ia)=—PbfCompound described in 105b′) are prepared by deprotecting the —Pbf groupof a compound of formula (VIIIy)

wherein Y is as above defined and A₂₃ is a radical of formula (IIa),(IIc) wherein R₁ is -Fmoc; R₂ is —C(O)OR_(2x) and binds the group—B—Y—ONO₂; R_(a) and R_(c) are R_(ia)NH(═NH)NH—(CH₂)₃—R_(ia) is the —Pbfprotective group;

105d) compounds (VIIIx) and (VIIIy) are prepared by reactingrespectively a compound of formula A₁₄ or A₁₅ described in 101d) withcompound (IIIg) or (IIIn) depending on the meaning of B, and applyingthe same procedure described in 4b) or 6b):

A₁₄ or A₁₅ Hal-W₁—OC(O)O—Y—ONO₂  (IIIg)

A₁₄ or A₁₅ Hal-W₁—OC(O)—Y—ONO₂  (IIIn)

wherein Hal, W₁ and Y are as above.

106. The compounds of general formula (I) wherein:

s′ and m are equal to 1;s″, m′ and m″ are equal to 0;Y and Y′ are as above defined;

B is:

A is a radical of formula (IIa), (IIc) or (IIt) wherein R₁ is —H, R₂ is—C(O)OR_(2x) and binds a group —B—Y—ONO₂;R_(a) of formula (IIa) and R_(c) of formula (IIc) are R_(h)NH(CH₂)_(p)—wherein p is an integer from 0 to 4, or R_(i)NH(═NH)NH—(CH₂)₃—, whereinR_(h) and R_(i) are R_(hh)—OC(O)— or R_(ii)—OC(O) and bind a group—Y′—ONO₂in formula (IIt) R₁ is —H, and R₂ is —C(O)OR_(2x) and binds a group—B—Y—ONO₂, d is 2 d′ is 1, R_(t) is —C(O)O—R_(tt) and binds a group—Y′—ONO₂;can be obtained as follows:

106a) R_(a)=R_(c) selected from R_(h)NH(CH₂)_(p)— wherein p is aninteger from 0 to 4, R_(h) is R_(hh)—OC(O)—:

by reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″, B,Y, Y′, Y″ are as above defined in 106, A is a radical of (IIa), (IIc) or(IIt) wherein R₂, d, d′, R_(t) are as defined in 106, R_(a) and R_(c)are selected from R_(h)NH(CH₂)_(p)— wherein p is an integer from 0 to 4,R_(h) is R_(hh)—OC(O)—; R₁ is —C(O)OC(CH₃)₃;with anhydrous or aqueous organic or inorganic acid to hydrolyze the—BOC protective groups following procedure well known in the literature.

106a′) R_(a)=R_(c) selected from R_(i)NH(═NH)NH—(CH₂)₃—, R_(i) isR_(ii)—OC(O)—;

by reacting a compound of formula (VIIIz)

wherein B, Y and Y′ are as above defined and A₂₄ is a radical of formula(IIa), (IIc) wherein R₁ is the -Fmoc protective group; R₂ is—C(O)OR_(2x) and binds a group —B—Y—ONO₂; R_(a) of formula (IIa) andR_(c) of formula (IIc) are R_(i)NH(═NH)NH—(CH₂)₃— wherein R_(i) isR_(ii)—OC(O)— and binds a group —Y′—ONO₂ by known procedure to removethe -Fmoc protective groups;

106b) R_(a)=R_(c) are selected from R_(h)NH(CH₂)_(p)— wherein p is aninteger from 0 to 4, R_(h) is —H

by reacting a compound of formula (I) obtained as described in 105c)with a compound of formula (IIIf)

wherein Act, B, Y and Y′ are as above defined and A is as defined in105b), using the same procedure described in 3b).

106b′) R_(a)=R_(c) selected from R_(i)NH(═NH)NH—(CH₂)₃—, R_(i) is —H:

by reacting a compound of formula (VIIIw) obtained as described in105c′) with a compound of formula (IIIf)

wherein B, Y and Y′ are as above defined and A₂₁ is as defined in105b′), using the same procedure described in 3b).

107. The compounds of general formula (I) wherein:

s is equal to 1;s′, s″, m, m′ and m″ are equal to 0;Y is as above defined;A is a radical of formula (IIa), (IIc) or (IIt) wherein R₁ is—C(O)—R_(1x) and binds a group —Y—ONO₂; R₂ is —COOHR_(a) of formula (IIa) and R_(c) of formula (IIc) are R_(h)NH(CH₂)_(p)—wherein p is an integer from 0 to 4, or R_(i)NH(═NH)NH—(CH₂)₃—, whereinR_(h) and R_(i) are —H;in formula (IIt) d is 2 d′ is 1, R_(t) is —H;can be obtained as follows:

107a) R_(a)=R_(c) selected from R_(h)NH(CH₂)_(p)— wherein p is aninteger from 0 to 4, R_(h) is —H

by reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″, Y,Y′, Y″ are as above defined in 107, A is a radical of (IIa), (IIc) or(IIt) wherein R₁, R₂, d, d′, are as defined in 107, R_(a) of formula(IIa) and R_(c) of formula (IIc) are selected from R_(h)NH(CH₂)_(p)—wherein p is an integer from 0 to 4, R_(h) is —C(O)OC(CH₃)₃;in formula (IIt) R_(t) is —C(O)OC(CH₂)₃;with anhydrous or aqueous organic or inorganic acid to hydrolyze the—BOC protective groups following procedure well known in the literature.

107a′) R_(a)=R_(c) selected from R_(i)NH(═NH)NH—(CH₂)₃—, R_(i) is —H;

reacting a compound of formula (VIIIaa)

A₂₅-Y—ONO₂  (VIIIaa)

wherein Y is as above defined and A₂₅ is a radical of formula (IIa),(IIc) wherein R₁, R₂ are as defined in 107, R_(a) of formula (IIa) andR_(c) of formula (IIc) are selected from R_(ia)NH(═NH)NH—(CH₂)₃—,wherein R_(ia) is the —Pbf protective group as already defined;with anhydrous or aqueous organic or inorganic acid to hydrolyze the—Pbf protective groups following procedure well known in the literature.

107b) compounds described in 107a) and 107a′) can be prepared byreacting a compound of formula A or a compound of formula A₂₆ with acompound of formula (IIIe)

wherein Act and Y are as above defined and:A is a compound of formula (IIa), (IIc) or (IIt) wherein R₁ is —H, R₂ is—COOH; R_(a) of formula (IIa) and R_(c) of formula (IIc) areR_(h)NH(CH₂)_(p)— wherein p is an integer from 0 to 4, R_(h) isC(O)OC(CH₃)₃; in formula (IIt) d and d′ are as defined in 107, R_(t) is—C(O)OC(CH₃)₃;A₂₆ is a compound of formula (IIa) or (IIc) wherein R₁ is —H, R₂ is—COOH; R_(a) of formula (IIa) and R_(c) of formula (IIc) areR_(ia)NH(═NH)NH—(CH₂)₃—, wherein R_(ia) is the —Pbf protective group asalready defined;using the same procedure described in 1b′).

Compounds A and A₂₆ are commercially available.

108. The compounds of general formula (I) wherein:

s is equal to 1;s′, s″, m, m′ and m″ are equal to 0;Y is as above defined;A is selected from (IIa), (IIc) and (IIt) wherein R₁ is —C(O)O—R_(1x)and binds a group —Y—ONO₂; R₂ is —COOHR_(a) of formula (IIa) and R_(c) of formula (IIc) are R_(h)NH(CH₂)_(p)—wherein p is an integer from 0 to 4, or R_(i)NH(═NH)NH—(CH₂)₃—, whereinR_(h) and R_(i) are —H;in formula (IIt) d is 2 d′ is 1, R_(t) is —H;can be obtained as follows:

108a) R_(a)=R_(c) selected from R_(h)NH(CH₂)_(p)— wherein p is aninteger from 0 to 4, R_(h) is —H

by reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″, Y,Y′, Y″ are as above defined in 108, A is a radical of (IIa), (IIc) or(IIt) wherein R₁, R₂, d, d′, are as defined in 108, R_(a) of formula(IIa) and R_(c) of formula (IIc) are selected from R_(h)NH(CH₂)_(p)—wherein p is an integer from 0 to 4, R_(h) is —C(O)OC(CH₃)₃;in formula (IIt) R_(t) is —C(O)OC(CH₃)₃;with anhydrous or aqueous organic or inorganic acid to hydrolyze the—BOC protective groups following procedure well known in the literature.

108a′) R_(a)=R_(c) selected from R_(i)NH(═NH)NH—(CH₂)₃—, R_(i) is —H;

reacting a compound of formula (VIIIab)

A₂₇-Y—ONO₂  (VIIIab)

wherein Y is as above defined and A₂₇ is a radical of (IIa), (IIc)wherein R₁, R₂ are as defined in 108, R_(a) of formula (IIa) and R_(c)of formula (IIc) are selected from R_(ia)NH(═NH)NH—(CH₂)₃—, whereinR_(ia) is the —Pbf protective group as already defined;with anhydrous or aqueous organic or inorganic acid to hydrolyze the—Pbf protective groups following procedure well known in the literature.

108b) compounds described in 108a) and 108a′) can be prepared

by reacting a compound of formula A or a compound of formula A₂₆ bothalready defined in 107b) with a compound of formula (IIIf)

wherein Act and Y are as above defined, using the same proceduredescribed in 3b).

109. The compounds of general formula (I) wherein:

s is equal to 1;s′, s″, m, m′ and m″ are equal to 0;Y is as above defined;A is selected from (IIa), (IIc) and (IIt) wherein R₁ is —H; R₂ is —COOH;R_(a) of formula (IIa) and R_(c) of formula (IIc) are R_(h)NH(CH₂)_(p)—wherein p is an integer from 0 to 4, or R_(i)NH(═NH)NH—(CH₂)₃—, whereinR_(h) and R_(i) are R_(hh)—C(O) or R_(ii)—C(O) and bind a group —Y—ONO₂;in formula (IIt) d is 2 d′ is 1, R_(t) is —C(O)—R_(tt), and binds agroup —Y—ONO₂;can be obtained as follows:

109a) by reacting a compound of formula (I) wherein s, s′, s″, m, m′,m″, Y, Y′, Y″ are as above defined in 109, A is a radical of (IIa),(IIc) or (IIt) wherein R₂, R_(a), R_(c), d, d′ and R_(t) are as definedin 109, R₁ is —C(O)OC(CH₃)₃;

with anhydrous or aqueous organic or inorganic acid to hydrolyze the—BOC protective groups following procedure well known in the literature.

109b) by reacting a compound of formula A with a compound of formula(IIIe)

A+Act(O)C—Y—ONO₂  (IIIe)

wherein Act and Y are as above defined and A is a radical of (IIa),(IIc) or (IIt) wherein R₁ is —C(O)OC(CH₃)₃; R₂ is —COOH;R_(a) of formula (IIa) and R_(c) of formula (IIc) are R_(h)NH(CH₂)_(p)—wherein p is an integer from 0 to 4, or R_(i)NH(═NH)NH—(CH₂)₃—, whereinR_(h) and R_(i) are —H;in formula (IIt) d and d′ are as defined in 109, R_(t) is —H;using the same procedure described in 1b′).

Compounds A are commercially available.

110. The compounds of general formula (I) wherein:

s is equal to 1;s′, s″, m, m′ and m″ are equal to 0;Y is as above defined;A is selected from (IIa), (IIc) and (IIt) wherein R₁ is —H; R₂ is —COOH;R_(a) of formula (IIa) and R_(c) of formula (IIc) are R_(h)NH(CH₂)_(p)—wherein p is an integer from 0 to 4, or R_(i)NH(═NH)NH—(CH₂)₃—, whereinR_(h) and R_(i) are R_(hh)—OC(O)— or R_(ii)—OC(O) and bind a group—Y—ONO₂;in formula (IIt) d is 2 d′ is 1, R_(t) is —C(O)O—R_(tt), and it binds agroup —Y—ONO₂;can be obtained as follows:

110a) by reacting a compound of formula (I) wherein s, s′, s″, m, m′,m″, Y, Y′, Y″ are as above defined in 110, A is a radical of (IIa),(IIc) or (IIt) wherein R₂, R_(a), R_(c), d, d′ and R_(t) are as definedin 110, R₁ is —C(O)OC(CH₃)₃;

with anhydrous or aqueous organic or inorganic acid to hydrolyze the—BOC protective groups following procedure well known in the literature.

110b) by reacting a compound of formula A with a compound of formula(IIIf)

A+Act(O)C—O—Y—ONO₂  (IIIf)

wherein Act and Y are as above defined and A is as defined in 109b),using the same procedure described in 3b).

111. The compounds of general formula (I) wherein:

s, s′ and m′ are equal to 1;s″, m, m″, are 0Y and Y′ are equal or different and are as above defined;

B is:

A is selected among:i) (IIa) wherein R₁ is —H, R₂ is —C(O)OR_(2x) and R₂ binds a groupB—Y′—ONO₂; R_(a) is selected from R_(bx)—C(O)—S—CH₂—, or R_(x)O—CH₂—,R_(x)O—CH(CH₃)—, (R_(x)O)-p-C₆H₄—CH₂—,4-(R_(x)O)-3,5-diiodobenzyl-4-(R_(x)O)-3-nitrobenzyl- wherein R_(x) isR_(xx)—C(O)— and R_(a) binds a group —Y—ONO₂;ii) (IIc) wherein R₁ is —H, R₂ is —C(O)OR_(2x) and R₂ binds a groupB—Y′—ONO₂; R_(c) is selected from R_(bx)—C(O)—S—CH₂—, or R_(x)O—CH₂—,R_(x)O—CH(CH₃)—, (R_(x)O)-p-C₆H₄—CH₂—,4-(R_(x)O)-3,5-diiodobenzyl-4-(R_(x)O)-3-nitrobenzyl- wherein R_(x) isR_(xx)—C(O)— and R_(c) binds a group —Y—ONO₂;iii) (IIs) wherein R₁ is —H, R₃ is —OC(O)R_(3x) and R₃ binds a group—Y—ONO₂; R_(s) is selected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂,R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—, wherein R_(g) is R_(gx)—O—, andR_(s) binds a group B—Y′—ONO₂;v) (IIn), wherein R₁ is —H, R₂ is —C(O)OR_(2x), R₂ binds a groupB—Y′—ONO₂; a is 1, b is 0 or 1; R_(x) is R_(xx)—C(O)— and R_(x) binds agroup —Y—ONO₂;can be prepared as follows:

111a) by reacting a compound of formula (I) wherein B, s, s′, s″, m, m′,m″, Y, Y′, Y″ are as above defined in 111, A is a radical of formula(IIa), (IIc), (IIs) or (IIu) wherein; R₂, R₃, a, b, R_(a), R_(c), R_(g)and R_(x) are as defined in 111; R₁ is —C(O)OC(CH₃)₃, with anhydrous oraqueous organic or inorganic acid to hydrolyze the —BOC protectivegroups following procedure well known in the literature.

111b) by reacting a compound of formula (I) obtained in 36b) with acompound of formula (IIIg) or (IIIn) depending on the meaning of B

wherein Y and Y′, Hal, W₁ are as above defined and in formula (I) A isselected among:i) (IIa) wherein R₁ is —C(O)OC(CH₃)₃, R₂ is —COOH, R_(a) is selectedfrom R_(bx)—C(O)—S—CH₂—, or R_(x)O—CH₂—, R_(x)O—CH(CH₂)—,(R_(x)O)-p-C₆H₄—CH₂—,4-(R_(x)O)-3,5-diiodobenzyl-4-(R_(x)O)-3-nitrobenzyl- wherein R_(x) isR_(xx)—C(O)— and R_(a) binds a group —Y—ONO₂;ii) (IIc) wherein R₁ is —C(O)OC(CH₃)₃, R₂ is —COOH, R_(c) is selectedfrom R_(bx)—C(O)—S—CH₂—, or R_(x)O—CH₂—, R_(x)O—CH(CH₂)—,(R_(x)O)-p-C₆H₄—CH₂—,4-(R_(x)O)-3,5-diiodobenzyl-4-(R_(x)O)-3-nitrobenzyl- wherein R_(x) isR_(xx)—C(O)— and R_(c) binds a group —Y—ONO₂;iii) (IIs) wherein R₁ is —C(O)OC(CH₃)₃, R₃ is —OC(O)R_(3x) and R₃ bindsa group —Y—ONO₂; R_(s) is selected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂,R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—, wherein R_(g) is —OH,v) (IIu) wherein R₁ is —C(O)OC(CH₃)₃, R₂ is —COOH, a is 1, b is 0 or 1;and R_(x) is R_(xx)—C(O)— and R_(x) binds a group —Y—ONO₂;following the same procedures described in 4b) or 6b).

112. The compounds of general formula (I) wherein:

s, s′and m′ are equal to 1;s″, m, m″, are 0Y and Y′ are equal or different and are as above defined;

B is:

A is selected among:i) (IIa) wherein R₁ is —H, R₂ is —C(O)OR_(2x) and R₂ binds a groupB—Y′—ONO₂; and R_(a) is selected from R_(bx)—OC(O)—S—CH₂—, orR_(x)O—CH₂—, R_(x)O—CH(CH₃)—, (R_(x)O)-p-C₆H₄—CH₂—,4-(R_(x)O)-3,5-diiodobenzyl-4-(R_(x)O)-3-nitrobenzyl- wherein R_(x) isR_(xx)—OC(O)— and R_(a) binds a group —Y—ONO₂;ii) (IIc) wherein R₁ is —H, R₂ is —C(O)OR_(2x) and R₂ binds a groupB—Y′—ONO₂; R_(c) is selected from R_(bx)—OC(O)—S—CH₂—, or R_(x)O—CH₂—,R_(x)O—CH(CH₃)—, (R_(x)O)-p-C₆H₄—CH₂—,4-(R_(x)O)-3,5-diiodobenzyl-4-(R_(x)O)-3-nitrobenzyl- wherein R_(x) isR_(xx)—OC(O)— and R_(c) binds a group —Y—ONO₂;iii) (IIs) wherein R₁ is —H, R₃ is —OC(O)O—R_(3x) and R₃ binds a group—Y—ONO₂; R_(s) is selected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂,R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—, wherein R_(g) is R_(gx)—O—, andR_(s) binds a group B—Y′—ONO₂;v) wherein R₁ is —H, R₂ is —C(O)OR_(2x), R₂ binds a group —B—Y′—ONO₂; ais 1; b is 0 or 1; R_(x) is R_(xx)—OC(O)— and R_(x) binds a group—Y—ONO₂;can be prepared as follows:

112a) by reacting a compound of formula (I) wherein B, s, s′, s″, m, m′,m″, Y, Y′, Y″ are as above defined in 112, A is a radical of formula(IIa), (IIc), (IIs) or (IIu) wherein; R₂, R₃, a, b, R_(a), R_(c), R_(g)and R_(x) are as defined in 112; R₁ is —C(O)OC(CH₃)₃ with anhydrous oraqueous organic or inorganic acid to hydrolyze the —BOC protectivegroups following procedure well known in the literature.

112b) by reacting a compound of formula (I) obtained in 37b) with acompound of formula (IIIg) or (IIIn) depending on the meaning of B

wherein Y and Y′, Hal, W₁ are as above defined and in formula (I) A isas above defined in 111b);following the same procedures described in 4b) or 6b).

113. The compounds of general formula (I) wherein:

s, s′and m′ are equal to 1;s″, m, m″, are 0Y and Y′ are equal or different and are as above defined;

B is:

A is selected among:i) (IIa) wherein R₁ is —H, R₂ is —C(O)OR_(2x) and R₂ binds a groupB—Y′—ONO₂; and R_(a) is selected from R_(bx)—NH(O)C—S—CH₂—, orR_(x)O—CH₂—, R_(x)O—CH(CH₃)—, (R_(x)O)-p-C₆H₄—CH₂—,4-(R_(x)O)-3,5-diiodobenzyl-4-(R_(x)O)-3-nitrobenzyl- wherein R_(x) isR_(xx)NH(O)C— and R_(a) binds a group —Y—ONO₂;ii) (IIc) wherein R₁ is —H, R₂ is —C(O)OR_(2x) and R₂ binds a groupB—Y′—ONO₂; R_(c) is selected from R_(bx)—NH(O)C—S—CH₂—, or R_(x)O—CH₂—,R_(x)O—CH(CH₃)—, (R_(x)O)-p-C₆H₄—CH₂—,4-(R_(x)O)-3,5-diiodobenzyl-4-(R_(x)O)-3-nitrobenzyl- wherein R_(x) isR_(xx)NH(O)C— and R_(c) binds a group —Y—ONO₂;iii) (IIs) wherein R₁ is —H, R₃ is —OC(O)—NH—R_(3x) and R₃ binds a group—Y—ONO₂; R_(s) is selected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH_(2f)R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—, wherein R_(g) is R_(gx)—O—, andR_(g) binds a group B—Y′—ONO₂;v) (IIu) wherein R₁ is —H, R₂ is —C(O)OR_(2x), and R₂ binds a groupB—Y′—ONO₂; a is 1; b is 0 or 1; R_(x) is R_(xx)—NHC(O)— and R_(x) bindsa group —Y—ONO₂;can be prepared as follows:

113a) by reacting a compound of formula (I) wherein B, s, s′, s″, m, m′,m″, Y, Y′, Y″ are as above defined in 113, A is a radical of formula(IIa), (IIc), (IIs) or (IIu) wherein; R₂, R₃, a, b, R_(a), R_(c), R_(g)and R_(x) are as defined in 113; R₁ is —C(O)OC(CH₃)₃ with anhydrous oraqueous organic or inorganic acid to hydrolyze the —BOC protectivegroups following procedure well known in the literature.

113b) by reacting a compound of formula (I) obtained in 38b) with acompound of formula (IIIg) or (IIIn) depending on the meaning of B

wherein Y and Y′, Hal, W₁ are as above defined and in formula (I) A isas above defined in 111b);following the same procedures described in 4b) or 6b).

114. The compounds of general formula (I) wherein:

s is equal to 1;m, m′, m″, s′ and s″ are 0Y is as above defined,A is a radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and(IIn) wherein R₁ is —C(O)—R_(1x) and it binds the group —Y—ONO₂, R₂ isequal to the group R₄

in formula (IIn) R_(n) is —C(O)—R_(nx), or is —(CH₂)₂—NH—R_(h) whereinR_(h) is —C(O)R_(hh) and it binds the group —Y—ONO₂R_(a) of formula (IIa) is selected in group a)R_(c) of formula (IIc) is selected in group a′)in formula (IIt) d is an integer from 3 to 5, d′ is 0;can be prepared as follows

114a) by reacting a compound of formula A with a compound of formula(IIIa) or a compound of formula (IIIe)

A+HOOC—Y—ONO₂  (IIIa)

A+Act-CO—Y—ONO₂  (IIIe)

wherein Y is as above defined and A is selected from (IIa)-(IIm),(IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein R₁ is —H and R₂ is as abovedefined in 114;in formula (IIn) R_(n) is H, or is —(CH₂)₂—NH—R_(h) wherein R_(h) is H;R_(a) of formula (IIa) is selected in group a);R_(c) of formula (IIc) is selected in group a′);in formula (IIt) d and d′ are as above defined;following the same procedure described in 1b) or 1b′).

114b) compounds A as above defined can be prepared by reactingcommercially available compounds of formula A₂ described in 1c) whereinA₂ is a radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and(IIn) wherein R₂ is —COOH or R_(2a) wherein R_(2a) is the group —COActas already described in 8, R₁ is —C(O)OC(CH₃)₃, R_(n) is —C(O)OC(CH₃)₃or is —(CH₂)₂—NH—C(O)OC(CH₃)₃, R_(a), R_(c), d and d′ are as defined in114, with compounds (IIIx) or (IIIy):

In case of (IIIx): in the presence of a inorganic or organic base in anaprotic polar or in an aprotic non-polar solvent such as DMF, THF orCH₂Cl₂ at temperatures range between 0° to 100° C.; In case of (IIIy)following the same procedure described in 8b) for R₂ equal to —COOH orequal to R_(2a) wherein R_(2a) is the group —COAct. Compound (IIIx) iscommercially available. Compound (IIIy) can be obtained from (IIIx) byfirst reacting with formic acid and TEA in acetonitrile and thenhydrolyzing the formyl ester with hydrochloric acid in methanol/water atroom temperature, as described for analogous compounds by Alexander inJ. Med. Chem. 1996, 39, 480-486.

115. The compounds of general formula (I) wherein:

s is equal to 1;m, m′, m″, s′ and s″ are 0Y is as above defined,A is a radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and(IIn) wherein R₁ is —C(O)O—R_(1x) and it binds the group —Y—ONO₂, R₂ isequal to R₄, wherein R₄ is as defined in 114;in formula (IIn) R_(n) is —C(O)O—R_(nx) or —(CH₂)₂—NH—R_(h)wherein R_(h) is —C(O)O—R_(hh), and it binds the group —Y—ONO₂R_(a) of formula (IIa) is selected in group a)R_(c) of formula (IIc) is selected in group a′)in formula (IIt) d is an integer from 3 to 5, d′ is 0;can be prepared as follows

115a) by reacting a compound of formula A with a compound of formula(IIIf)

A+Act-(O)C—O—Y—ONO₂  (IIIf)

wherein A is as above reported in 114a), Act and Y are as alreadydefined, following the same procedure described in 3b).

116. The compounds of general formula (I) wherein:

s is equal to 1;s′, s″, m, m′, m″, are 0Y is as above defined;A is selected among:(IIa) wherein R₁ is —H, R₂ is —C(O)OR_(2x) and R₂ binds a group —Y—ONO₂;R_(a) is selected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—,R_(g)C(O)(CH₂)₄—, wherein R_(g) is equal to R_(gg) and is equal to:

(IIc) wherein R₁ is —H, R₂ is —C(O)OR_(2x) and R₂ binds a group —Y—ONO₂;R_(c) is selected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—,R_(g)C(O)(CH₂)₄—, wherein R_(g) is equal to R_(gg) and is as abovedefinedcan be prepared as follows:

116a) by reacting a compound of formula (VIIIa)

A₂₈a Y ONO₂  (IXa)

wherein Y is as above defined and A_(28a) is a radical of formula (IIa),(IIc), wherein R₂ is as above defined in 116; R₁ is R_(1a) and is theFmoc group; R_(a) and R_(c) are R_(gg)C(O)CH₂—NH—, R_(gg)C(O)CH₂,R_(gg)C(O)(CH₂)₂—, R_(gg)C(O)(CH₂)₄—, wherein R_(gg) is as above definedby known procedure to remove the -Fmoc protective groups;

116b) by reacting a compound of formula A₂₈ with a compound of formula(IIIi)

A₂₈+HO—Y—ONO₂  (IIIi)

wherein Y is as above defined and A₂₈ is a compound of formula (IIa) or(IIc) wherein R₁ is R_(1a) and is the Fmoc group; R₂ is —COOH, R_(a) andR_(c) are selected from R_(gg)C(O)CH₂—NH—, R_(gg)C(O)CH₂,R_(gg)C(O)(CH₂)₂—, R_(gg)C(O)(CH₂)₄—, wherein R_(gg) is as above definedin 116;following the same procedure described in 8b).

116c) by reacting a compound A₂₉

A₂₉→A₂₈

wherein R₁ is R_(1a) and is the Fmoc group; R₂ is —C(O)OC(CH₃)₃; R_(a)and R_(c) are selected from R_(gg)C(O)CH₂—NH—, R_(gg)C(O)CH₂,R_(gg)C(O)(CH₂)₂—, R_(gg)C(O)(CH₂)₄—, wherein R_(gg) is as above definedin 116 with anhydrous or aqueous organic or inorganic acid as well knownin the literature to remove the t-butyl ester.

116d) by reacting a compound A₃₀

A₃₀→A₂₉

wherein R₁ is R_(1a) and is the Fmoc group; R₂ is —C(O)OC(CH₃)₃; R_(a)and R_(c) are selected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂,R_(g)C(O)(CH₃)₃—, R_(g)C(O)(CH₂)₄—, wherein R_(g) is —OH with compounds(IIIx) or (IIIy) as described in 114b). Compounds A₃₀ are commerciallyavailable.

117. The compounds of general formula (I) wherein:

s is equal to 1;s′, s″, m, m′, m″, are 0Y is as above defined;A is a radical of formula(IIa) wherein R₁ is —H, R₂ is —C(O)NHR_(2xx) or —C(O)N(CH₃)R_(2xx) andR₂ binds a group —Y—ONO₂; R_(a) is selected from R_(g)C(O)CH₂—NH—,R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₄—, R_(g)C(O)(CH₂)₄—, wherein R_(g) isR_(gg) and is as defined in 116; or(IIc) wherein R₁ is —H, R₂ is —C(O)NHR_(2xx) or —C(O)N(CH₃)R_(2xx) andR₂ binds a group —Y—ONO₂; R_(c) is selected from R_(g)C(O)CH₂—NH—,R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—, wherein R_(g) isR_(gg) and is as defined in 116; can be prepared as follows:

117a) by reacting a compound of formula (IXb)

A₃₁-Y—ONO₂  (IXb)

wherein Y is as above defined and A₃₁ is a radical of formula (IIa),(IIc), wherein R₂ is as above defined in 117; R₁ is R_(1a) and is theFmoc group; R_(a) and R_(c) are R_(gg)C(O)CH₂—NH—, R_(gg)C(O)CH₂,R_(gg)C(O)(CH₂)₂—, R_(gg)C(O)(CH₂)₄—, wherein R_(gg) is as above definedby known procedure to remove the -Fmoc protective groups; 117b) byreacting a compound of formula A₂₈ with a compound of formula (IIIo)

A₂₈+W₃NH—Y—ONO₂→  (IXb)

wherein Y is as above defined, W₃ is as above defined and A₂₈ is asdefined in 116b),following the same procedure described in 7b).

118. The compounds of general formula (I) wherein:

s and m are equal to 1;s′, s″, m′, m″, are 0Y is as above defined;

B is:

A is a radical selected among:

(IIa) wherein R₈ is —H, R₂ is —C(O)OR_(2x) and R₂ binds a group—B—Y—ONO₂; R_(a) is selected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂,R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—, wherein R_(g) is R_(gg) and is asdefined in 116;(IIc) wherein R₈ is —H, R₂ is —C(O)OR_(2x) and R₂ binds a group—B—Y—ONO₂; R_(c) is selected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂,R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—, wherein R_(g) is R_(gg) and is asdefined in 116; can be prepared as follows:

118a) by reacting a compound of formula (VIIIc)

A_(28a)-B—Y—ONO₂  (IXc)

wherein B and Y are as above defined and A_(28a) is as defined in 116a)a radical of formula (IIa), (IIc), wherein R₂ is as above defined in118; R₁ is R_(1a) and is the Fmoc group; R_(a) and R_(c) areR_(gg)C(O)CH₂—NH—, R_(gg)C(O)CH₂, R_(gg)C(O)(CH₂)₂—, R_(gg)C(O)(CH₂)₄—,wherein R_(gg) is as above defined by known procedure to remove the-Fmoc protective groups;

118b) compound (IXc) are prepared by reacting a compound of formula A₂₈with a compound of formula (IIIg) or (IIIn) depending on the meaning ofB

A₂₈+Hal-W₁—OC(O)O—Y—ONO₂  (IIIg)

A₂₈+Hal-W₁—OC(O)—Y—ONO₂  (IIIn)

wherein Y, Hal, W₈ are as above defined and A₂₈ is as defined in 116b),following the same procedures described in 4b) or 6b).

119. The compounds of general formula (I) wherein:

s is equal to 1;s′, s″, m, m′, m″, are 0Y is as above defined;A is selected among:(IIa) wherein R₈ is —H, R₂ is equal to R₄ and is as defined in 114;R_(a) is selected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—,R_(g)C(O)(CH₂)₄—, wherein R_(g) is R_(gx)—O—, and R_(g) binds a group—Y—ONO₂;(IIc) wherein R₁ is —H, R₂ is equal to R₄ and is as defined in 114;R_(c) is selected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—,R_(g)C(O)(CH₂)₄—, wherein R_(g) is R_(gx)—O—, and R_(g) binds a group—Y—ONO₂,can be prepared as follows:

119a) by reacting a compound of formula (Xa)

A₃₂-Y—ONO₂  (Xa)

wherein Y is as above defined and A₃₂ is a radical of formula (IIa),(IIc), wherein R_(a) and R_(c) are as above defined in 119; R₁ is—R_(1a) and is the Fmoc group; R₂ is R₄ and is as defined in 114;following procedure well known in the literature to remove the Fmocgroup.

119b) by reacting a compound of formula A₃₃ with a compound of formula(IIIi)

(IIIi)

A₃₃+HO—Y—ONO₂→  (Xa)

wherein Y is as above defined and A₃₃ is a radical of formula (IIa),(IIc) wherein R₁ is —R_(1a) and is the Fmoc group; R₂ is R₄ and is asdefined in 114; R_(a) and R_(c) are selected from R_(g)C(O)CH₂—NH—,R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—, wherein R_(g) is —OH;following the same procedure described in 8b).

119c) by reacting a compound A₃₄

A₃₄→A₃₃

wherein R₁ is R_(1a) and is the Fmoc group; R₂ is R₄; R_(a) and R_(c)are selected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—,R_(g)C(O)(CH₂)₄—, wherein R_(g) is —C(O)OC(CH₃)₃ with anhydrous oraqueous organic or inorganic acid as well known in the literature toremove the t-butyl ester.

119d) by reacting a compound A₃₅

A₃₅→A₃₄

wherein R₁ is R_(1a) and is the Fmoc group; R₂ is —COOH; R_(a) and R_(c)are selected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—,R_(g)C(O)(CH₂)₄—, wherein R_(g) is —C(O)OC(CH₃)₃ with compounds (IIIx)or (IIIy) as described in 114b). Compounds A₃₅ are commerciallyavailable.

120. The compounds of general formula (I) wherein:

s is equal to 1;s′, s″, m, m′, m″, are 0Y is as above defined;A is selected among:(IIa) wherein R₁ is —H, R₂ is R₄ and is as defined in 114; R_(a) isselected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—,R_(g)C(O)(CH₂)₄—, wherein R_(g) is R_(gxx)—NH— or R_(gxx)—N(CH₃)— andR_(g) binds a group —Y—ONO₂;(IIc) wherein R₁ is —H, R₂ is R₄ and is as defined in 114; R_(c) isselected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—,R_(g)C(O)(CH₂)₄—, wherein R_(g) is R_(gxx)—NH— or R_(gxx)—N(CH₃)— andR_(g) binds a group —Y—ONO₂;can be prepared as follows:

120a) by reacting a compound of formula (Xb)

A₃₆-Y—ONO₂  (Xb)

wherein Y is as above defined and A₃₆ is a radical of formula (IIa),(IIc), wherein R_(a) and R_(c) are as above defined in 120; R₁ is R_(1a)and is the Fmoc group; R₂ is R₄ and is as defined in 114; followingprocedure well known in the literature to remove the Fmoc group.

120b) by reacting a compound of formula A₃₃ with a compound of formula(IIIo):

(IIIo)

A₃₃+W₃NH—Y—ONO₂→  (Xb)

wherein Y and W₃ are as above defined and A₃₃ is as defined in 119b)following the same procedure described in 7b).

121. The compounds of general formula (I) wherein:

s and m are equal to 1;s′, s″, m′, m″, are 0Y is as above defined;

B is:

A is selected among:(IIa) wherein R₁ is —H, R₂ is R₄ and is as defined in 114; R_(a) isselected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—,R_(g)C(O)(CH₂)₄—, wherein R_(g) is R_(gx)—O—, and R_(g) binds a group—B—Y—ONO₂;(IIc) wherein R₁ is —H, R₂ is R₄ and is as defined in 114; R_(c) isselected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—,R_(g)C(O)(CH₂)₄—, wherein R_(g) is R_(gx)—O—, and R_(g) binds a groupB—Y—ONO₂;can be prepared as follows:

121a) by reacting a compound of formula (Xc)

A₃₇-B—YONO₂  (Xc)

wherein B and Y are as above defined and A₂₇ is a radical of formula(IIa), (IIc), wherein R_(a) and R_(c) are as above defined in 121; R₁ isR_(1a) and is the Fmoc group; R₂ is R₄ and is as defined in 114;following procedure well known in the literature to remove the Fmocgroup.

121b) compounds (Xc) are prepared by reacting a compound of formula A₃₃with a compound of formula of formula (IIIg) or (IIIn) depending on themeaning of B

A₃₃+Hal-W₁—OC(O)O—Y—ONO₂  (IIIg)

A₃₃+Hal-W₁—OC(O)—Y—ONO₂  (IIIn)

wherein Y, Hal, W₁ are as above defined and A₃₃ is as defined in 119b),following the same procedures described in 4b) or 6b).

122. The compounds of general formula (I) wherein:

s and s′ are equal to 1;s″, m, m′, m″, are 0Y and Y′ can be equal or different and are as above defined;A is selected among:(IIa) wherein R₁ is —C(O)—R_(1x) and binds a group —Y′—ONO₂; R₂ is—C(O)OR_(2x) and binds a group —Y—ONO₂; R_(a) is selected fromR_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—,wherein R_(g) is equal to R_(gg) and is as defined in 116;(IIc) wherein R₁ is —C(O)—R_(1x) and binds a group —Y′—ONO₂; R₂ is—C(O)OR_(2x) and binds a group —Y—ONO₂; R_(c) is selected fromR_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—,wherein R_(g) is equal to R_(gg) and is as defined in 116; can beprepared as follows:

122a) by reacting a compound of formula (I) prepared as described in116. with a compound of formula (IIIe):

wherein Act, Y and Y′ are as above defined and A is a radical of formula(IIa), (IIc), wherein R₁ is —H, R₂ is —C(O)OR_(2x) and binds a group—Y—ONO₂; R_(a) and R_(c) are selected from R_(gg)C(O)CH₂—NH—,R_(gg)C(O)CH₂, R_(gg)C(O)(CH₂)₂—, R_(gg)C(O)(CH₂)₄—, wherein R_(gg) isas above defined;following the same procedures described in 1b′).

123. The compounds of general formula (I) wherein:

s and s′ are equal to 1;s″, m, m′, m″, are 0Y and Y′ can be equal or different and are as above defined;A is selected among:(IIa) wherein R₁ is —C(O)O—R_(1x) and binds a group —Y′—ONO₂; R₂ is—C(O)OR_(2x) and binds a group —Y—ONO₂; R_(a) is selected fromR_(g)C(O)CH₂—NH, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—,wherein R_(g) is equal to R_(gg) and is as defined in 116;(IIc) wherein R₁ is —C(O)O—R_(1x) and binds a group —Y′—ONO₂; R₂ is—C(O)OR_(2x) and binds a group —Y—ONO₂; R_(c) is selected fromR_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—,wherein R_(g) is equal to R_(gg) and is as defined in 116; can beprepared as follows:

123a) by reacting a compound of formula (I) prepared as described in116. with a compound of formula (IIIf):

wherein Act, Y and Y′ are as above defined and A is as defined in 122a);following the same procedures described in 3b).

124. The compounds of general formula (I) wherein:

s and s′ are equal to 1;s″, m, m′, m″, are 0Y and Y′ can be equal or different and are as above defined;A is selected among:(IIa) wherein R₁ is —C(O)—R_(1x) and binds a group —Y′—ONO₂; R₂ is—C(O)NHR_(2xx) or —C(O)N(CH₃)R_(2xx) and binds a group —Y—ONO₂; R_(a) isselected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—,R_(g)C(O)(CH₂)₄—, wherein R_(g) is equal to R_(gg) and is as defined in116; (IIc) wherein R₁ is —C(O)—R_(1x) and binds a group —Y′—ONO₂; R₂ is—C(O)NHR_(2xx) or —C(O)N(CH₃)R_(2xx) and binds a group —Y—ONO₂; R_(c) isselected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—,R_(g)C(O)(CH₂)₄—, wherein R_(g) is equal to R_(gg) and is as defined in116; can be prepared as follows:

124a) by reacting a compound of formula (I) prepared as described in117. with a compound of formula (IIIe):

wherein Act, Y and Y′ are as above defined and A is a radical of formula(IIa), (IIc), wherein R₁ is —H, R₂ is —C(O)NHR_(2xx) or —C(O)NCH₃R_(2xx)and binds a group —Y—ONO₂; R_(a) and R_(c) are selected fromR_(gg)C(O)CH₂—NH—, R_(gg)C(O)CH₂, R_(gg)C(O)(CH₂)₂—, R_(gg)C(O)(CH₂)₄—,wherein R_(gg) is as above defined;following the same procedures described in 1b′).

125. The compounds of general formula (I) wherein:

s and s′ are equal to 1;s″, m, m′, m″, are 0Y and Y′ can be equal or different and are as above defined;A is selected among:(IIa) wherein R₁ is —C(O)O—R_(1x) and binds a group —Y′—ONO₂; R₂ is—C(O)NHR_(2xx) or —C(O)N(CH₃)R_(2xx) and binds a group —Y—ONO₂; R_(a) isselected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—,R_(g)C(O)(CH₂)₄—, wherein R_(g) is equal to R_(gg) and is as defined in116;(IIc) wherein R₁ is —C(O)O—R_(1x) and binds a group —Y′—ONO₂; R₂ is—C(O)NHR_(2xx) or —C(O)N(CH₃)R_(2xx) and binds a group —Y—ONO₂; R_(c) isselected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—,R_(g)C(O)(CH₂)₄—, wherein R_(g) is equal to R_(gg) and is as defined in116; can be prepared as follows:

125a) by reacting a compound of formula (I) prepared as described in117. with a compound of formula (IIIf):

wherein Act, Y and Y′ are as above defined and A is as above defined in124a), following the same procedures described in 3b).

126. The compounds of general formula (I) wherein:

s, s′ and m are equal to 1;s″, m′, m″, are 0Y and Y′ can be equal or different and are as above defined;

B is:

A is selected among:(IIa) wherein R₁ is —C(O)—R_(1x) and binds a group —Y′—ONO₂; R₂ is—C(O)OR_(2x) and binds a group —B—Y—ONO₂; R_(a) is selected fromR_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—,wherein R_(g) is equal to R_(gg) and is as defined in 116;(IIc) wherein R₁ is —C(O)—R_(1x) and binds a group —Y′—ONO₂; R₂ isC(O)OR_(2x) and binds a group —B—Y—ONO₂; R_(a) is selected fromR_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—,wherein R_(g) is equal to R_(gg) and is as defined in 116;can be prepared as follows:

126a) by reacting a compound of formula (I) prepared as described in118. with a compound of formula (IIIe):

wherein Act, B, Y and Y′ are as above defined and A is a radical offormula (IIa), (IIc), wherein R₁ is —H, R₂ is —C(O)OR_(2x) and binds agroup B—Y—ONO₂; R_(a) and R_(c) are selected from R_(gg)C(O)CH₂—NH—,R_(gg)C(O)CH₂, R_(gg)C(O)(CH₂)₂—, R_(gg)C(O)(CH₂)₄—, wherein R_(gg) isas above defined;following the same procedures described in 1b′).

127. The compounds of general formula (I) wherein:

s, s′ and m are equal to 1;s″, m′, m″, are 0Y and Y′ can be equal or different and are as above defined;

B is:

A is selected among:(IIa) wherein R₁ is —C(O)O—R_(1x) and binds a group —Y′—ONO₂; R₂ is—C(O)OR_(2x) and binds a group —B—Y—ONO₂; R_(a) is selected fromR_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—,wherein R_(g) is equal to R_(gg) and is as defined in 116;(IIc) wherein R₁ is —C(O)O—R_(1x) and binds a group —Y′—ONO₂; R₂ is—C(O)OR_(2x) and binds a group —B—Y—ONO₂; R_(c) is selected fromR_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—,wherein R_(g) is equal to R_(gg) and is as defined in 116; can beprepared as follows:

127a) by reacting a compound of formula (I) prepared as described in118. with a compound of formula (IIIf):

wherein Act, B, Y and Y′ are as above defined and A is as defined in126a), following the same procedures described in 3b).

128. The compounds of general formula (I) wherein:

s and s′ are equal to 1;s″, m, m′, m″, are 0Y and Y′ can be equal or different and are as above defined;A is selected among:(IIa) wherein R₁ is —C(O)—R_(1x) and it binds a group —Y′—ONO₂; R₂ isequal to R₄ and is as defined in 114; R_(a) is selected fromR_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—,wherein R_(g) is R_(gx)—O—, and binds a group —Y—ONO₂(IIc) wherein R₁ is —C(O)—R_(1x) and binds a group —Y′—ONO₂; R₂ is equalto R₄ and is as defined in 114; R_(c) is selected from R_(g)C(O)CH₂—NH—,R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—, wherein R_(g) isR_(gx)—O—, and binds a group —Y—ONO₂;can be prepared as follows:

128a) by reacting a compound of formula (I) prepared as described in119. with a compound of formula (IIIe):

wherein Act, Y and Y′ are as above defined and A is a radical of formula(IIa), (IIc), wherein R₁ is —H, R₂ is equal to R₄; R_(a) and R_(c) areselected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—,R_(g)C(O)(CH₂)₄—, wherein R_(g) is R_(gx)—O—, and binds a group —Y—ONO₂following the same procedures described in 1b′).

129. The compounds of general formula (I) wherein:

s and s′ are equal to 1;s″, m, m′, m″, are 0Y and Y′ can be equal or different and are as above defined;A is selected among:(IIa) wherein R₁ is —C(O)O—R_(1x) and it binds a group —Y′—ONO₂; R₂ isequal to R₄ and is as defined in 114; R_(a) is selected fromR_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—,wherein R_(g) is R_(gx)—O—, and binds a group —Y—ONO₂(IIc) wherein R₁ is —C(O)O—R_(1x) and binds a group —Y′—ONO₂; R₂ isequal to R₄ and is as defined in 114; R_(c) is selected fromR_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—,wherein R_(g) is R_(gx)—O—, and binds a group —Y—ONO₂;can be prepared as follows:

129a) by reacting a compound of formula (I) prepared as described in119. with a compound of formula (IIIf):

wherein Act, Y and Y′ are as above defined and A is a radical of formula(IIa), (IIc), wherein R₁ is —H, R₂ is equal to R₄; R_(a) and R_(c) areselected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—,R_(g)C(O)(CH₂)₄—, wherein R_(g) is R_(gx)O— and R_(g) binds a group—Y—ONO₂,following the same procedures described in 3b).

130. The compounds of general formula (I) wherein:

s and s′ are equal to 1;s″, m, m′, m″, are 0Y and Y′ can be equal or different and are as above defined;A is selected among:(IIa) wherein R₁ is —C(O)—R_(1x) and it binds a group —Y′—ONO₂; R₂ isequal to R₄ and is as defined in 114; R_(a) is selected fromR_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—,wherein R_(g) is R_(gxx)—NH— or R_(gxx)—N(CH₃)— and R_(a) binds a group—Y—ONO₂(IIc) wherein R₁ is —C(O)—R_(1x) and it binds a group —Y′—ONO₂; R₂ isequal to R₄ and is as defined in 114; R_(c) is selected fromR_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—,wherein R_(g) is R_(gxx)—NH— or R_(gxx)—N(CH₃)— and R_(c) binds a group—Y—ONO₂;can be prepared as follows:

130a) by reacting a compound of formula (I) prepared as described in120. with a compound of formula (IIIe):

wherein Act, Y and Y′ are as above defined and A is a radical of formula(IIa), (IIc), wherein R₁ is —H, R₂ is—equal to R₄; R_(a) and R_(c) areselected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—,R_(g)C(O)(CH₂)₄—, wherein R_(g) is R_(gxx)—NH— or R_(gxx)—N(CH₃)— andbinds a group —Y—ONO₂following the same procedures described in 1b′).

131. The compounds of general formula (I) wherein:

s and s′ are equal to 1;s″, m, m′, m″, are 0Y and Y′ can be equal or different and are as above defined;A is selected among:(IIa) wherein R₁ is —C(O)O—R_(1x) and binds a group —Y′—ONO₂; R₂ isis—equal to R₄ and is as defined in 114; R_(a) is selected fromR_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—,wherein R_(g) is R_(gxx)—NH— or R_(gxx)—N(CH₃)— and binds a group—Y—ONO₂(IIc) wherein R₁ is —C(O)O—R_(1x) and binds a group —Y′—ONO₂; R₂ isis—equal to R₄ and is as defined in 114; R_(c) is selected fromR_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—,wherein R_(g) is R_(g)—NH— or R_(gxx)—N(CH₃)— and binds a group —Y—ONO₂;can be prepared as follows:

131a) by reacting a compound of formula (I) prepared as described in120. with a compound of formula (IIIf):

wherein Act, Y and Y′ are as above defined and A is as defined in 130a),following the same procedures described in 3b).

132. The compounds of general formula (I) wherein:

s, s′ and m are equal to 1;s″, m′, m″, are 0Y and Y′ can be equal or different and are as above defined;

B is:

A is selected among:(IIa) wherein R₁ is —C(O)—R_(1x) and binds a group —Y′—ONO₂; R₂ is equalto R₄ and is as defined in 114; R_(a) is selected from R_(g)C(O)CH₂—NH—,R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—, wherein R_(g) isR_(gx)O—, and binds a group —B—Y—ONO₂;(IIc) wherein R₁ is —C(O)—R_(1x) and binds a group —Y′—ONO₂; R₂ is—equalto R₄ and is as defined in 114; R_(c) is selected from R_(g)C(O)CH₂—NH—,R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—, wherein R_(g) isR_(gx)O—, and binds a group —B—Y—ONO₂;can be prepared as follows:

132a) by reacting a compound of formula (I) prepared as described in121. with a compound of formula (IIIe):

wherein Act, B, Y and Y′ are as above defined and A is a radical offormula (IIa), (IIc), wherein R₁ is —H, R₂ is equal to R₄; R_(a) andR_(c) are selected from R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂,R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—, wherein R_(g) is R_(gx)O— and bindsa group B—Y—ONO₂;following the same procedures described in 1b′).

133. The compounds of general formula (I) wherein:

s, s′ and m are equal to 1;s″, m′, m″, are 0Y and Y′ can be equal or different and are as above defined;

B is:

A is selected among:(IIa) wherein R₁ is —C(O)O—R_(1x) and binds a group —Y′—ONO₂; R₂ isequal to R₄ and is as defined in 114; R_(a) is selected fromR_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—,wherein R_(g) is R_(gx)O—, and binds a group —B—Y—ONO₂;(IIc) wherein R₁ is —C(O)O—R_(1x) and it binds a group —Y′—ONO₂; R₂ isequal to R₄ and is as defined in 114; R_(c) is selected fromR_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—,wherein R_(g) is R_(gx)O— and R_(g) binds a group —B—Y—ONO₂;can be prepared as follows:

133a) by reacting a compound of formula (I) prepared as described in121. with a compound of formula (IIIf):

wherein Act, B, Y and Y′ are as above defined and A is as defined in132a), following the same procedures described in 3b).

134. The compounds of general formula (I) wherein:

s and s′ are equal to 1;s″, m, m′ and m″ are equal to 0;Y and Y′ are equal and are as above defined;A is selected from (IIa), (IIc) or (IIt) wherein R₁ is —C(O)—R_(1x) andit binds a group —Y—ONO₂ or a group —Y′—ONO₂, R₂ is equal to R₄ and isas defined in 114; R_(a) of formula (IIa) and R_(c) of formula (IIc) areR_(h)NH(CH₂)_(p)— wherein p is an integer from 0 to 4, orR_(i)NH(═NH)NH—(CH₂)₃—, and R_(h) and R_(i) are R_(hh)—C(O) orR_(ii)—C(O)— and R_(a) and R_(c) bind a group —Y—ONO₂ or a group—Y′—ONO₂;in formula (IIt) R₁ is —C(O)—R_(1x) and it binds a group —Y—ONO₂ or agroup —Y′—ONO₂, R₂ is equal to R₄ and is as defined in 114; d is 2 d′ is1, R_(t) is —C(O)—R_(tt) and it binds a group —Y—ONO₂ or a group—Y′—ONO₂;can be prepared as follows:

134a) by reacting a compound of formula A with a compound of formula(IIIe)

A+Act-(O)C—Y—ONO₂  (IIIe)

wherein Act and Y are as above defined and A is a compound of formula(IIa), (IIc) or (IIt) wherein R₁ is —H and R₂ is equal to R₄;R_(a) of formula (IIa) and R_(c) of formula (IIc) are R_(h)NH(CH₂)_(p)—wherein p is an integer from 0 to 4, or R_(i)NH(═NH)NH—(CH₂)₃—, andR_(h) and R_(i) are —H;in formula (IIt) R₁ is —H, R₂ is R₄; d is 2 d′ is 1, R_(t) is —H; usinga ratio A/(IIIe) 1:2 and applying the same procedure described in 1b′).

134b) by reacting a compound of formula A₃₈

A₃₈→A

wherein A₃₈ is a compound of formula (IIa), (IIc) or (IIt) wherein R₁ is—C(O)OC(CH₃)₃ and R₂ is equal to R₄;R_(a) of formula (IIa) and R_(c) of formula (IIc) are R_(h)NH(CH₂)_(p)—wherein p is an integer from 0 to 4 and R_(h) is —C(O)OC(CH₃)₃; orR_(ia)NH(═NH)NH—(CH₂)₃—, wherein R_(ia) is the —Pbf group as alreadydescribed;in formula (IIt) R₁ is —C(O)OC(CH₃)₃, R₂ is R₄; d is 2 d′ is 1, R_(t) is—C(O)OC(CH₃)₃;with organic or inorganic acid as already described to hydrolyze the—BOC protecting groups;

134c) by reacting commercially available compounds of formula A₃₉ withcompounds (IIIx) or (IIIy) using the procedures described in 114b)

A₃₉+(IIIx)→A₃₈

A₃₉+(IIIy)→A₃₈

wherein A₃₉ is a radical of formula (IIa), (IIc) or (IIt) wherein R₁ is—C(O)OC(CH₃)₃ and R₂ is equal to —COOH or R_(2a) wherein R_(2a) is asdescribed in 8b); d is 2 d′ is 1, R_(t) is —C(O)OC(CH₃)₃; R_(a) offormula (IIa) and R_(c) of formula (IIc) are:R_(h)NH(CH₂)_(p)— wherein p is an integer from 0 to 4, R_(h) is—C(O)OC(CH₃)₃;or R_(ia)NH(═NH)NH—(CH₂)₃— wherein R_(ia) is as previously defined.

135. The compounds of general formula (I) wherein:

s and s′ are equal to 1;s″, m, m′ and m″ are equal to 0;Y and Y′ are equal and are as above defined;A is a radical selected from (IIa), (IIc) and (IIt) wherein R₁ is—C(O)O—R_(1x) and binds a group —Y—ONO₂ or a group —Y′—ONO₂, R₂ is equalto R₄ and is as defined in 114;R_(a) of formula (IIa) and R_(c) of formula (IIc) are R_(h)NH(CH₂)_(p)—wherein p is an integer from 0 to 4, or R_(i)NH(═NH)NH—(CH₂)₃—, andR_(h) and R_(i) are R_(hh)—OC(O)— or R_(ii)—OC(O)— and R_(a) and R_(c)bind a group —Y—ONO₂ or a group —Y′—ONO₂;in formula (IIt) R₁ is —C(O)O—R_(1x) and binds a group —Y—ONO₂ or agroup —Y′—ONO₂, R₂ is equal to R₄ and is as defined in 114; d is 2 d′ is1, R_(t) is —C(O)O—R_(tt) and binds a group —Y—ONO₂ or a group —Y′—ONO₂;can be prepared as follows:

135a) by reacting a compound of formula A with a compound of formula(IIIf)

A+Act-(O)C—O—Y—ONO₂  (IIIf)

wherein Act and Y are as above defined and A is as defined in 134a)using a ratio A/(IIIf) 1:2 and applying the same procedure described in3b).

136. The compounds of general formula (I) wherein:

s is equal to 1;s′, s″, m, m′ and m″ are equal to 0;Y is as above defined;A is a radical of formula (IIa), (IIc) or (IIt) wherein R₁ is—C(O)—R_(1x) and binds a group —Y—ONO₂; R₂ is equal to R₄ and is asdefined in 114; R_(a) of formula (IIa) and R_(c) of formula (IIc) areR_(h)NH(CH₂)_(p)— wherein p is an integer from 0 to 4, orR_(i)NH(═NH)NH—(CH₂)₃—, wherein R_(h) and R_(i) are —H;in formula (IIt) d is 2 d′ is 1, R_(t) is —H;can be obtained as follows:

136a) R_(a)=R_(c) selected from R_(h)NH(CH₂)_(p)— wherein p is aninteger from 0 to 4, R_(h) is —H

by reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″, Y,Y′, Y″ are as above defined in 136, A is a radical of (IIa), (IIc) or(IIt) wherein R₁, R₂, d, d′, are as defined in 136, R_(a) of formula(IIa) and R_(c) of formula (IIc) are selected from R_(h)NH(CH₂)_(p)—wherein p is an integer from 0 to 4, R_(h) is —C(O)OC(CH₃)₃;in formula (IIt) R_(t) is —C(O)OC(CH₃)₃;with anhydrous or aqueous organic or inorganic acid to hydrolyze the—BOC protective groups following procedure well known in the literature.

136a′) R_(a)=R_(c) selected from R_(i)NH(═NH)NH—(CH₂)₃—, R_(i) is —H;reacting a compound of formula (Xd)

A₄₀-Y—ONO₂  (Xd)

wherein Y is as above defined and A₄₀ is a radical of formula (IIa),(IIc) wherein R₁ and R₂ are as defined in 136, R_(a) of formula (IIa)and R_(c) of formula (IIc) are selected from R_(ia)NH(═NH)NH—(CH₂)₃—,wherein R_(ia) is the —Pbf protective group as already defined;with anhydrous or aqueous organic or inorganic acid to hydrolyze the—Pbf protective groups following procedure well known in the literature.

136b) compounds described in 136a) and 136a′) are respectively obtainedby reacting a compound of formula A₄₁ or a compound of formula A₄₂ witha compound of formula (IIIe)

(IIIe)

A₄₁+Act(O)C—Y′—ONO₂→  (I)

(IIIe)

A₄₂+Act(O)C—Y′—ONO₂→  (Xd)

wherein Act and Y are as above defined and:A₄₁ is a compound of formula (IIa), (IIc) or (IIt) wherein R₁ is —H, R₂is equal to R₄; R_(a) of formula (IIa) and R_(c) of formula (IIc) areR_(h)NH(CH₂)_(p)— wherein p is an integer from 0 to 4, R_(h) is—C(O)OC(CH₃)₃; in formula (IIt) d and d′ are as defined in 136, R_(t) is—C(O)OC(CH₃)₃;A₄₂ is a compound of formula (IIa) or (IIc) wherein R₁ is —H, R₂ isequal to R₄; R_(a) of formula (IIa) and R_(c) of formula (IIc) areR_(ia)NH(═NH)NH—(CH₂)₃—, wherein R_(ia) is the —Pbf protective group asalready defined;using the same procedure described in 1b′).

136c) compounds A₄₁ and A₄₂ are respectively obtained by reacting acompound of formula A or a compound of formula A₂₆, both described in107b) with a compound of formula (IIIx) or (IIIy) as already describedin 114b).

137. The compounds of general formula (I) wherein:

s is equal to 1;s′, s″, m, m′ and m″ are equal to 0;Y is as above defined;A is selected from (IIa), (IIc) and (IIt) wherein R₁ is —C(O)O—R_(1x)and binds a group —Y—ONO₂; R₂ is equal to R₄ and is as defined in 114;R_(a) of formula (IIa) and R_(c) of formula (IIc) are R_(h)NH(CH₂)_(p)—wherein p is an integer from 0 to 4, or R_(i)NH(═NH)NH—(CH₂)₃—, whereinR_(h) and R_(i) are —H;in formula (IIt) d is 2 d′ is 1, R_(t) is —H;can be obtained as follows:

137a) R_(a)=R_(c) selected from R_(h)NH(CH₂)_(p)— wherein p is aninteger from 0 to 4, R_(h) is —H

by reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″, Y,Y′, Y″ are as above defined in 137, A is a radical of (IIa), (IIc) or(IIt) wherein R₁, R₂, d, d′, are as defined in 137, R_(a) of formula(IIa) and R_(c) of formula (IIc) are selected from R_(h)NH(CH₂)_(p)—wherein p is an integer from 0 to 4, R_(h) is —C(O)OC(CH₃)₃;in formula (IIt) R_(t) is —C(O)OC(CH₃)₃;with anhydrous or aqueous organic or inorganic acid to hydrolyze the—BOC protective groups following procedure well known in the literature.

137a′) R_(a)=R_(c) selected from R_(i)NH(═NH)NH—(CH₂)₃—, R_(i) is —H;

reacting a compound of formula (Xe)

A₄₃-Y—ONO₂  (Xe)

wherein Y is as above defined and A₄₃ is a radical of (IIa), (IIc)wherein R₁ and R₂ are as defined in 137, R_(a) of formula (IIa) andR_(c) of formula (IIc) are selected from R_(ia)NH(═NH)NH—(CH₂)₃—,wherein R_(ia) is the Pbf protective group as already defined;with anhydrous or aqueous organic or inorganic acid to hydrolyze the—Pbf protective groups following procedure well known in the literature.

137b) compounds described in 137a) and 137a′) are respectively obtainedby reacting a compound of formula A₄₁ or a compound of formula A₄₂ bothalready defined in 136b) with a compound of formula (IIIf)

(IIIf)

A₄₁+Act(O)C—O—Y—ONO₂→  (I)

(IIIf)

A₄₂+Act(O)C—O—Y—ONO₂→  (Xe)

wherein Act and Y are as above defined, using the same proceduredescribed in 3b).

138. The compounds of general formula (I) wherein:

s is equal to 1;s′, s″, m, m′ and m″ are equal to 0;Y is as above defined;A is selected from (IIa), (IIc) and (IIt) wherein R₁ is —H; R₂ is equalto R₄ and is as defined in 114; R_(a) of formula (IIa) and R_(c) offormula (IIc) are R_(h)NH(CH₂)_(p)— wherein p is an integer from 0 to 4,or R_(i)NH(═NH)NH—(CH₂)₃—, wherein R_(h) and R_(i) are R_(hh)—C(O)— orR_(ii)—C(O)—, and bind a group —Y—ONO₂;in formula (IIt) d is 2 d′ is 1, R_(t) is —C(O)—R_(tt), and binds agroup —Y—ONO₂;can be obtained as follows:

138a) by reacting a compound of formula (I) wherein s, s′, s″, m, m′,m″, Y, Y′, Y″ are as above defined in 138, A is a radical of (IIa),(IIc) or (IIt) wherein R₂, R_(a), R_(c), d, d′ and R_(t) are as definedin 138, R₁ is —C(O)OC(CH₃)₃;

with anhydrous or aqueous organic or inorganic acid to hydrolyze the—BOC protective groups following procedure well known in the literature.

138b) by reacting a compound of formula A with a compound of formula(IIIe)

A+Act(O)C—Y—ONO₂  (IIIe)

wherein Act and Y are as above defined and A is a radical of (IIa),(IIc) or (IIt) wherein R₁ is —C(O)OC(CH₃)₃; R₂ is equal to R₄; R_(a) offormula (IIa) and R_(c) of formula (IIc) are R_(h)NH(CH₂)_(p)— wherein pis an integer from 0 to 4, or R_(i)NH(═NH)NH—(CH₂)₃—, wherein R_(h) andR_(i) are —H;in formula (IIt) d and d′ are as defined in 138, R_(t) is —H;using the same procedure described in 1b′).

138c) by reacting a compound of formula A with a compound of formula(IIIx) or (IIIy)

A+(IIIx)

A+(IIIy)

Wherein A is a radical of formula (IIa), (IIc) or (IIt) wherein R₁ is—C(O)OC(CH₃)₃; R₂ is —COOH or R_(2a) wherein R_(2a) is the group —COActas already described in 8; R_(a) of formula (IIa) and R_(c) of formula(IIc) are R_(h)NH(CH₂)_(p)— wherein p is an integer from 0 to 4, orR_(i)NH(═NH)NH—(CH₂)₃—, wherein R_(h) and R_(i) are —H;in formula (IIt) d and d′ are as defined in 138, R_(t) is —H; using thesame procedures described in 114b).

139. The compounds of general formula (I) wherein:

s is equal to 1;s′, s″, m, m′ and m″ are equal to 0;Y is as above defined;A is selected from (IIa), (IIc) and (IIt) wherein R₁ is —H; R₂ is equalto R₄ and is as defined in 114;R_(a) of formula (IIa) and R_(c) of formula (IIc) are R_(h)NH(CH₂)_(p)—wherein p is an integer from 0 to 4, or R_(i)NH(═NH)NH—(CH₂)₃—, whereinR_(h) and R_(i) are R_(hh)—OC(O)— or R_(ii)—OC(O)—, and bind a group—Y—ONO₂;in formula (IIt) d is 2 d′ is 1, R_(t) is —C(O)O—R_(tt), and it binds agroup —Y—ONO₂;can be obtained as follows:

139a) by reacting a compound of formula (I) wherein s, s′, s″, m, m′,m″, Y, Y′, Y″ are as above defined in 139, A is a radical of (IIa),(IIc) or (IIt) wherein R₂, R_(a), R_(c), d, d′ and R_(t) are as definedin 139, R₁ is —C(O)OC(CH₃)₃;

with anhydrous or aqueous organic or inorganic acid to hydrolyze the—BOC protective groups following procedure well known in the literature.

139b) by reacting a compound of formula A described in 138b) with acompound of formula (IIIf)

A+Act(O)C—O—Y—ONO₂  (IIIf)

wherein Act and Y are as above defined using the same proceduredescribed in 3b).

EXAMPLE 1

(S)-4-(nitrooxy)butyl 2-amino-6-(tert-butoxycarbonylamino)hexanoate(corresponding to compound 18) Step A: (S)-4-(nitrooxy)butyl1-(9H-fluoren-9-yl)-13,13-dimethyl-3,11-dioxo-2,12-dioxa-4,10-diazatetradecane-5-carboxylate

Commercial N(α)-Fmoc-N(ε)-Boc-L-lysine pentafluorophenyl ester (6.51mmol) and 4-(nitrooxy)-1-butanol (6.55 mmol) were dissolved in DMF (12ml) and the mixture was cooled to 0° C. N,N-dimethylaminopyridine (DMAP)(6.55 mmol) were added and the reaction was slowly warmed to roomtemperature and stirred for 4 hours. Then the mixture was concentrateunder reduced pressure and diluted with EtOAc, washed with 5% aqueousNa₂HPO₄ and brine. The organic layer was dried over sodium sulphate andconcentrated under reduced pressure.

The residue was purified by flash chromatography (n-hexan/EtOAc 70:30 aseluent) yielding the title compound (2.52 g, 66%).

Step B: (S)-4-(nitrooxy)butyl2-amino-6-(tert-butoxycarbonylamino)hexanoate

To a solution of S)-4-(nitrooxy)butyl1-(9H-fluoren-9-yl)-13,13-dimethyl-3,11-dioxo-2,12-dioxa-4,10-diazatetradecane-5-carboxylate(2.52 g, 4.30 mmol) in CH₃CN (30 ml), piperidine (2.12 ml, 21.5 mmol)was added in the dark, the reaction was stirred at rt for 25 min. Thenthe mixture was concentrated to a small volume and diluted with EtOAc(150 ml) and washed with 5% aqueous NaHPO₄ (2×70 ml). The organic layerwas dried over sodium sulphate and concentrated under reduced pressure.

The residue was purified by flash chromatography (CH₂Cl₂/MeOH 98:2 aseluent), yielding the title compound (0.960 g, 61%).

¹H-NMR (DMSO-d₆): 6.78 (1H, t), 4.55 (2H, t), 4.07 (2H, m), 3.26 (2H,t), 2.87 (1H, m), 1.73-1.65 (4H, m), 1.64-1.40 (2H, m), 1.37 (9H, s),1.36-1.22 (4H, s).

EXAMPLE 2

2-Amino-3-tert-butoxy-3-oxopropyl 4-(nitrooxy)butanoate (correspondingto compound 405) Step A: tert-butyl2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-hydroxypropanoate

To a solution of commercial N-Fmoc-L-serine (1.5 g, 4.58 mmol) in EtOAc(40 ml), a solution of t-butyl 2,2,2-trichloroacetimidate (4.00 g, 18.32mmol) in cyclohexane (18 ml) was added dropwise. After stirring at roomtemperature for 24 hrs, the solution was evaporated and the residue waspurified by flash chromatography (n-Hexane/EtOAc 70:3), yielding thetitle compound (1.20 g, 68%).

Step B:2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-tert-butoxy-3-oxopropyl4-(nitrooxy)butanoate

To a solution of2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-tert-butoxy-3-oxopropyl4-(nitrooxy)butanoate (1.20 g, 3.13 mmol), 4-(nitrooxy)butyric acidpentafluorophenyl ester (1.18 g, 3.76 mmol) and scandiumtrifluoromethanesulfonate (0.308 g, 0.626 mmol) in CH₂Cl₂ (25 ml) cooledto 0° C., was added N,N-dimethylaminopyridine (DMAP) (0.459 g, 3.76mmol). The resulting mixture was stirred at room temperature for 18hours. Then it was diluted with CH₂Cl₂ and washed with 5% aqueousNa₂HPO₄ and brine. The organic layer was dried over sodium sulphate andconcentrated under reduced pressure.

The residue was purified by flash chromatography (n-hexane/EtOAc 70:30as eluent) affording the title compound (1.26 g, 78%).

Step C: 2-Amino-3-tert-butoxy-3-oxopropyl 4-(nitrooxy)butanoate

To a solution of2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-tert-butoxy-3-oxopropyl4-(nitrooxy)butanoate (1.26 g, 2.45 mmol) in CH₃CN (15 ml), piperidine(1.21 ml, 12.2 mmol) was added in the dark, the reaction was stirred atroom temperature for 25 min. Then the mixture was concentrated to asmall volume and diluted with EtOAc (80 ml) and washed with 5% aqueousNaHPO₄. The organic layer was dried over sodium sulphate andconcentrated under reduced pressure. The residue was purified by flashchromatography (CH₂Cl₂/MeOH 98:2 as eluent) yielding the title compound(0.500 g, 70%).

¹H-NMR (CDCl₃): 6.49, 4.61-4.50 (3H, m), 3.95 (2H, d), 2.43 (2H, t),2.22-2.08 (2H, m), 1.05 (9H, s).

EXAMPLE 3 1-tert-Butyl2-(4-(nitrooxymethyl)benzyl)pyrrolidine-1,2-dicarboxylate (correspondingto compound 7) Step A: 1-tert-butyl2-(4-(chloromethyl)benzyl)pyrrolidine-1,2-dicarboxylate

N-Boc-L-proline (2.47 g, 11.5 mmol) and 4-(chloromethyl)benzyl alcohol(1.50 g, 9.58 mmol) were dissolved in CH₂Cl₂ (50 ml) and the mixture wascooled to 0° C. N-Ethyl-N′-(3-dimethylaminopropyl)carbodiimide (EDC)(2.75 g, 14.4 mmol) and N,N-dimethylaminopyridine (DMAP) (0.235 g, 1.92mmol) were added and the reaction was slowly warmed to room temperatureand stirred for 4 hours. Then the mixture was diluted with CH₂Cl₂ (200ml) and washed with 5% aqueous NaHCO₃, 5% aqueous Na₂HPO₄ and brine. Theorganic layer was dried over sodium sulphate and concentrated underreduced pressure. The residue was purified by flash chromatography(n-hexane/EtOAc 80:20 as eluent) affording the title compound. (2.98 g,88%).

Step B: 1-tert-Butyl2-(4-(nitrooxymethyl)benzyl)pyrrolidine-1,2-dicarboxylate

To a solution of 1-tert-butyl2-(4-(chloromethyl)benzyl)pyrrolidine-1,2-dicarboxylate (0.630 g, 1.78mmol) in CH₃CN (13 ml), AgNO₃ (0.756 g, 4.45 mmol) was added and thereaction was heated in a microwave apparatus (150° C., 20 min). Theformed salts were filtered off and the solvent was concentrated, thenthe residue was diluted with EtOAc (100 ml) and washed with brine. Theorganic layer was dried over sodium sulphate and concentrated underreduced pressure yielding the title compound (0.655 g, 96%).

¹H-NMR (CDCl₃): 7.41 (4H, d), 5.44 (2H, s), 5.30-5.10 (2H, m), 4.42-4.27(2H, m), 3.57-3.42 (2H, m), 2.30-2.15 (1H, m), 2.00-1.85 (3H, m),1.48-1.35 (9H, m).

EXAMPLE 4

4-[(nitrooxy)methyl]benzyl pyrrolidine-2-carboxylate hydrochloride(corresponding to compound 3)

To a solution of 1-tert-Butyl2-(4-(nitrooxymethyl)benzyl)pyrrolidine-1,2-dicarboxylate, obtained inExample 3, (0.543 g, 1.43 mmol) in CH₂Cl₂ (14 ml) cooled to 0° C.,HCl_(gas) was bubbled for 2 hours. The solvent was concentrated and theresidue was treated with diethyl ether, affording the title compound(0.446 g, 99%.

¹H-NMR (CDCl₃): 9.16 (bs), 7.40 (4H, d), 5.43 (2H, s), 5.31-5.17 (2H,m), 4.52 (1H, m), 3.52 (2H, m), 2.49-2.38 (1H, m), 2.20-2.00 (3H, m).

EXAMPLE 5

4-(nitrooxy)butyl 2-(tert-butoxycarbonylamino)acetate (corresponding tocompound 16)

Applying the same procedure described in Example 1, starting fromcommercially available N-Boc-L-glycine, N-hydroxysuccinimido ester (2.33g, 8.56 mmol), the title compound was obtained. (3.00 g, 80%).

¹H-NMR (CDCl₃): 5.04 (1H, bt), 4.49 (2H, t), 4.20 (2H, t), 3.91 (2H, d),1.81 (4H, m), 1.46 (9H, s).

EXAMPLE 6

4-(nitrooxy)butyl 2-aminoacetate hydrochloride (corresponding tocompound 21)

The title compound was obtained as a white solid starting from4-(nitrooxy)butyl 2-(tert-butoxycarbonylamino)acetate, prepared asdescribed in Example 5 following the procedure described in Example 4(2.34 g, quantitative yield).

¹H-NMR (CDCl₃): 4.53 (2H, t), 4.29 (2H, t), 4.04 (2H, d), 3.74 (2H, d),1.84 (4H, m).

EXAMPLE 7 4-(Nitrooxy)butyl2-(tert-butoxycarbonylamino)-3-methylbutanoate (corresponding tocompound 149) Step A: 4-chlorobutyl2-(tert-butoxycarbonylamino)-3-methylbutanoate

N-Boc-L-valine (3.48 g, 16.0 mmol), 4-chloro-1-butanol (3.47 g, 32.0mmol) and N-hydroxybenzotriazole (HOBT) (3.24 g, 24.0 mmol) weredissolved in CH₂Cl₂ (80 ml) and the mixture was cooled to 0° C.N-Methylmorpholine (NMM) (3.24 g, 32.0 mmol) andN,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-yl)uroniumhexafluorophosphate (HBTU) (6.67 g, 17.6 mmol) were added and thereaction was slowly warmed to room temperature and stirred for 24 hours.Then the mixture was diluted with CH₂Cl₂ (200 ml) and washed with 5%aqueous NaHCO₃, HCl 1N and brine. The organic layer was dried oversodium sulphate and concentrated under reduced pressure. The residue waspurified by flash chromatography (n-hexane/EtOAc 90:10) affording thetitle compound (2.98 g, 64%).

Step B: 4-(Nitrooxy)butyl 2-(tert-butoxycarbonylamino)-3-methylbutanoate

To a solution of 4-chlorobutyl2-(tert-butoxycarbonylamino)-3-methylbutanoate (0.630 g, 1.78 mmol) inCH₃CN (13 ml), AgNO₃ (0.756 g, 4.45 mmol) was added and the reaction washeated in a microwave apparatus (150° C., 20 min). The formed salts werefiltered off and the solvent was concentrated. Then the residue wasdiluted with EtOAc (100 ml) and washed with brine, dried over sodiumsulphate and concentrated under reduced pressure yielding the titlecompound (0.655 g).

¹H-NMR (CDCl₃): 5.00 (1H, d), 4.50 (2H, t), 4.24-4.16 (3H, m), 2.20-2.09(1H, m), 1.90-1.74 (4H, m), 1.46 (9H, s), 0.99 (3H, d), 0.92 (3H, d).

EXAMPLE 8

tert-butyl 2-(4-(nitrooxy)butylamino)-2-oxoethylcarbamate (correspondingto compound (12)) Step A: tert-butyl2-(4-hydroxybutylamino)-2-oxoethylcarbamate

4-Amino-1-butanol (0.686 g, 7.70 mmol) and triethylamine (0.779 g, 7.70mmol) were dissolved in CH₂Cl₂ (40 ml) and the mixture was cooled to 0°C. A suspension of commercial N-Boc-glycine N-hydroxysuccinimido estere(2.10 g; 7.70 mmol) in CH₂Cl₂ (40 ml) was added and the reaction wasslowly warmed to room temperature and stirred for 24 hours. Then themixture was diluted with CH₂Cl₂ (150 ml) and washed with 5% aqueousNa₂HPO₄ and brine. The aqueous layer was extracted twice with CH₂Cl₂ andtwice with a mixture of EtOAc/MeOH 98:2. The organic layers were driedover sodium sulphate and concentrated under reduced pressure. Theresidue was purified by flash chromatography (n-hexane/i-prOH 80:20)affording the title compound (2.16 g).

Step B: 2-(4-(nitrooxy)butylamino)-2-oxoethylcarbamate

To a solution of tert-butyl 2-(4-hydroxybutylamino)-2-oxoethylcarbamate(2.16 g, 8.77 mmol), tetraethylammonium nitrate (3.37 g, 17.54 mmol) and2,6-di-tert-butyl-4-methylpyridine (2.71 g, 13.16 mmol) in CH₂Cl₂ (60ml) cooled to −70° C. and under nitrogen, a solution oftrifluoromethansulfonic anhydride (2.72 g, 9.65 mmol) in CH₂Cl₂ (40 ml)was added drop wise. The resulting mixture was stirred for 3 hours at−65° C. Then the mixture was slowly warmed to room temperature, dilutedwith CH₂Cl₂ and washed with 5% aqueous Na₂HPO₄. The organic layer wasdried over sodium sulphate and concentrated under reduced pressure.

The residue was purified by flash chromatography CH₂Cl₂/CH₃CN 70:30 aseluent) affording the title compound (2.04 g, 80%).

¹H-NMR (CDCl₃): 6.30 (1H, s), 5.15 (1H, s), 4.48 (2H, t), 3.79 (2H, d),3.37-3.31 (2H, m), 1.80-1.74 (2H, m), 1.67-1.62 (2H, m), 1.63 (9H, s).

EXAMPLE 9 4-(2-Aminoacetamido)butyl nitrate hydrochloride (correspondingto compound 23)

The title compound was obtained as a white solid from tert-butyl

2-(4-(nitrooxy)butylamino)-2-oxoethylcarbamate (Example 8) following theprocedure described in Example 4. (1.58 g, quantitative yield).

¹H-NMR (CDCl₃): 8.55 (1H, s), 8.17 (2H, s), 4.54 (2H, t), 3.55-3.48 (2H,m), 3.18-3.12 (2H, m), 1.72-1.65 (2H, m), 1.53-1.48 (2H, m).

EXAMPLE 10

(2S,3aS,6aS)-4-(Nitrooxy)butyloctahydrocyclopenta[b]pyrrole-2-carboxylate (corresponding to compound512) Step A: (2S,3aS,6aS)-1-(9H-fluoren-9-yl)methyl 2-benzylhexahydrocyclopenta[b]pyrrole-1,2(2H)-dicarboxylate

To a solution of commercial (2S,3aS,6aS)-benzyloctahydrocyclopenta[b]pyrrole-2-carboxylatehydrochloride (1.00 g, 3.60mmol) and TEA (1.15 ml, 7.92 mmol) in CH₃CN (15 ml) cooled in an icebath 9-fluorenylmethoxycarbonyl chloride (1.01 g, 4.25 mmol) was added.The resulting mixture was stirred at room temperature overnight. Thenthe mixture was concentrated and diluted with CH₂Cl₂ (50 ml), washedwith a solution of NaH₂PO₄ 5% (2×30 ml) and brine (1×30 ml). The organicphase was dried over sodium sulphate and concentrated under reducedpressure to give an oil that slowly crystallized on storage affordingthe title compound (1.68 g, 100%).

Step B:(2S,3aS,6aS)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)octahydrocyclopenta[b]pyrrole-2-carboxylicacid

To a solution of (2S,3aS,6aS)-1-(9H-fluoren-9-yl)methyl 2-benzylhexahydrocyclopenta[b]pyrrole-1,2(2H)-dicarboxylate (1.68 g, 3.6 mmol)in EtOH 95% (15 ml) was added Palladium on carbon 10% (0.2 g, 0.18 mmol)and cyclohexene (3.5 ml, 36 mmol). The resulting mixture was refluxedfor 7 h. The solvent was evaporated and the crude was diluted withCH₂Cl₂ (20 ml). The suspension was filtered on celite and the organicphase was evaporated under vacuum. The residue was purified by flashchromatography (CH₂Cl₂/CH₃CN 50:50) to give the title compound as awhite foam (0.5 g, 37%)

Step C: (2S,3aS,6aS)-1-(9H-fluoren-9-yl)methyl 2-(4-chlorobutyl)hexahydrocyclopenta[b]pyrrole-1,2(2H)-dicarboxylate

(2S,3aS,6aS)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)octahydrocyclopenta[b]pyrrole-2-carboxylic acid (0.250 g, 0.66 mmol) and4-chloro-1-butanol (0.1 ml, 0.99 mmol) were dissolved under nitrogen inCH₂Cl₂ (5 ml) and the mixture was cooled to 0° C.N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC)(0.190 g, 0.99 mmol) and N,N-dimethylaminopyridine (DMAP) (0.016 g, 0.13mmol) were added and the reaction was slowly warmed to room temperatureand stirred for 4 h. Then the mixture was diluted with CH₂Cl₂ (10 ml)and washed with 5% aqueous NaHCO₃, 5% aqueous Na₂HPO₄ and brine. Theorganic layer was dried over sodium sulphate, concentrated under reducedpressure and purified by flash chromatography (n-hexane/EtOAc 80:20 aseluent) affording the title compound as an oil (0.14 g, 45%)

Step D: (2S,3aS,6aS)-1-(9H-fluoren-9-yl)methyl 2-(4-(nitrooxy)butyl)hexahydrocyclopenta[b]pyrrole-1,2(2H)-dicarboxylate

To a solution of (2S,3aS,6aS)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)octahydrocyclopenta[b]pyrrole-2-carboxylic acid (0.13 g, 0.27 mmol) inCH₃CN (1.7 ml), AgNO₃ (0.118 g, 0.69 mmol) was added and the reactionwas heated to 150° C. for 20 min in a microwave apparatus. The formedsalts were filtered off and the solvent was concentrated affording thetitle compound as a yellow solid (0.133 g, 100%).

To a solution of (2S,3aS,6aS)-1-(9H-fluoren-9-yl)methyl2-(4-(nitrooxy)butyl)hexahydrocyclopenta[b]pyrrole-1,2(2H)-dicarboxylate (0.133 g, 0.27 mmol)in CH₃CN (2 ml), piperidine (133 μl, 1.35 mmol) was added in the dark;the reaction was stirred at room temperature for 25 min. Then thesolution was evaporated, diluted with pH 3 aqueous buffer and theaqueous phase was extracted with hexane. The solution was basified to pH9 and finally extracted with diethyl ether. The organic layer was driedover sodium sulphate and concentrated under reduced pressure affordingthe title compound as an oil (0.04 g, 50%).

¹H-NMR (DMSO-d₆): 4.55 (2H, t); 4.13-3.96 (3H, m); 3.81 (1H, m); 3.68(1H, bs); 2.66-2.51 (1H, m); 2.34-2.19 (1H, m); 1.81-1.31 (11H, m).

EXAMPLE 11

(2S,3aS,6aS)-4-(nitrooxymethyl)benzyl octahydrocyclopenta[b]pyrrole-2-carboxylate (corresponding to compound 520)

The title compound was prepared following the procedure described inExample 10 using 4-(chloromethyl)benzyl alcohol instead of4-chloro-1-butanol in Step C.

¹H-NMR (DMSO-d₆): 7.51-7.21 (4H, m); 5.47 (2H, s); 5.09 (2H, s) 4.10(1H, m); 3.82 (1H, m); 3.68 (1H, m); 2.62 (1H, m); 2.38 (1H, m);1.92-1.05 (9H, m)

EXAMPLE 12

4-[(nitrooxy)methyl]benzyl-2-amino-6-(tert-butoxycarbonylamino)hexanoate(corresponding to compound 24)

The title compound was prepared following procedure already described inExamples 1 and 11 (0.010 g, 10%).

¹H-NMR (DMSO-d₆): 7.48-7.61 (8H, m); 6.78 (1H, t); 5.54 (2H, s); 5.15(2H, s); 4.07 (1H, m); 2.87 (1H, m); 1.73-1.65 (2H, m); 1.36-1.22 (13H,m).

EXAMPLE 13

4-(nitrooxy)butyl 2-(tert-butoxycarbonylamino)-3-hydroxypropanoate(corresponding to compound (45))

Starting from Boc-L-serine and following the procedure described inExample 3 the title was obtained as an oil (0.350 g, 48%).

¹H-NMR (CDCl₃): 5.44 (1H, bs); 4.50 (2H, t); 4.38 (1H, m); 4.25 (2H, m);3.97 (2H, m); 1.84 (4H, m); 1.47 (9H, s).

EXAMPLE 14 1-tert-butyl2-(4-(nitrooxy)butyl)pyrrolidine-1,2-dicarboxylate

Starting from Boc-L-Proline and 4-chloro-1-butanol and following theprocedure described in Example 3 the title compound was obtained as anoil.

¹H-NMR (CDCl₃): 4.50 (2H, t), 4.10-4.40 (3H, m), 3.65-3.33 (2H, m),2.34-1.70 (8H, m), 1.45 (9H, d).

EXAMPLE 15

1-tert-butyl 2-(3-(nitrooxy)propyl)pyrrolidine-1,2-dicarboxylate

Starting from Boc-L-Proline and 3-bromo-1-propanol and following theprocedure described in Example 3 the title compound was obtained as anoil.

¹H-NMR (CDCl₃): 4.56-4.52 (2H, m); 4.31-4.19 (3H, m); 3.57-3.35 (2H, m);2.28-1.80 (6H, m); 1.43 (9H, d).

EXAMPLE 16

2,2-dimethyl-15-(nitrooxy)-4,9-dioxo-3,8,10,13-tetraoxa-5-azapentadecane-6-carboxylicacid (Corresponding to Compound 400)

Into a solution of N-Boc-L-Serine (1.66 g, 8.12 mmol), di-isopropylethylamine (DIPEA) (1.41 ml, 8.12 mmol), N,N-dimethylaminopyridine (DMAP)(1.19 g, 9.74 mmol) and scandium triflate (1.20 g, 2.43 mmol) in CH₂Cl₂(40 ml), cooled to −10° C., a solution of 2-[2-(nitrooxy)ethoxy]ethyl4-nitrophenyl carbonate in CH₂Cl₂ (40 ml) was added drop-wise. Thereaction was slowly warmed to room temperature and stirred for 24 h.Then the organic phase was washed with pH 3 aqueous buffer andconcentrated under reduced pressure. The crude was partitioned betweenaqueous 5% aqueous Na₂HPO₄ and diethyl ether and extracted twice withdiethyl ether. The aqueous phase was acidified to pH 3 and extractedwith CH₂Cl₂. The organic phase was finally dried over sodium sulphateand concentrated under reduced pressure to give the title compound as anoil. (2.4 g, 80%)

¹H-NMR (CDCl₃): 5.54 (1H, bs); 4.63 (2H, m); 4.52 (3H, m); 4.29 (2H, m);3.86-3.69 (4H, m); 1.46 (9H, s).

EXAMPLE 17

2-(tert-butoxycarbonylamino)-4-methylpentyl 4-hydroxybutanoate(corresponding to compound (510)) Step A:2-(tert-butoxycarbonylamino)-4-methylpentyl 4-bromobutanoate

tert-Butyl 1-hydroxy-4-methylpentan-2-ylcarbamate (2.00 g, 9.20 mmol)and 4-bromo-butyric acid (2.57 g, 15.38 mmol) were dissolved in CH₂Cl₂(40 ml) and the mixture was cooled to 0° C. EDC (4.20 g, 21.90 mmol) andDMAP (0.27 g, 2.21 mmol) were added and the reaction was slowly warmedto room temperature and stirred overnight. Then the reaction was treatedwith a solution of 5% aqueous NaH₂PO₄ (100 ml). The organic layer waswashed with a solution of 10% aqueous Na₂CO₃ (100 ml) and brine, driedover Na₂SO₄, filtered and concentrated. The obtained crude clear oilcorresponding to the title compound (3.30 g) was used without anyfurther purification.

Step B: 2-(tert-Butoxycarbonylamino)-4-methylpentyl4-(nitrooxy)butanoate

To a solution of crude 2-(tert-butoxycarbonylamino)-4-methylpentyl4-bromobutanoate (3.30 g) in CH₃CN (60 ml), AgNO₃ (4.20 g, 24.52 mmol)was added. The resulting solution (divided into 5 vials) was heated in amicrowave apparatus (120° C., 9 minutes). Then the formed salts werefiltered off, the solvent was concentrated and the residue purified byflash chromatography (n-hexane/EtOAc 80:20 as eluent) affording thetitle compound (1.05 g, yield: 33.5%) as a clear oil.

¹H-NMR (CDCl₃): 4.54 (2H, t); 4.48-4.34 (1H, m); 2.49 (2H, t); 2.18-1.99(2H, m); 1.79-1.57 (1H, m); 1.39-1.22 (2H, m); 1.00-0.86 (6H, m).

EXAMPLE 18

2-Amino-4-methylpentyl 4-(nitrooxy)butanoate hydrochloride(corresponding to compound 507)

The title compound was prepared from2-(tert-butoxycarbonylamino)-4-methylpentyl 4-(nitrooxy)butanoate(described in Example 17) following the procedure described in Example 4(0.71 g, 90%).

¹H-NMR (DMSO-d₆): 4.56 (2H, t); 4.27-4.22 (1H, m); 4.11-4.06 (1H, m);3.39-3.32 (2H, m); 2.51 (2H, t); 2.01-1.92 (2H, m); 1.75-1.68 (1H, m);1.51-1.38 (2H, m); 0.90 (6H, d).

EXAMPLE 19

4-[(Nitrooxy)methyl]benzyl2-(tert-butoxycarbonylamino)-4-phenylbutanoate (corresponding tocompound 13)

The title compound was prepared as a clear oil from2-(tert-butoxycarbonylamino)-4-phenylbutanoic acid following proceduredescribed in Example 3.

¹H-NMR (CDCl₃): 7.34 (4H, m); 5.07-5.04 (1H, m); 4.49 (2H, t); 4.36-4.34(1H, m); 4.23-4.11 (2H, m); 2.70 (2H, t); 2.19-2.11 (1H, m); 2.02-1.94(1H, m); 1.92-1.76 (4H, m); 1.61 (9H, s).

EXAMPLE 20

3-[(Nitrooxy)methyl]phenyl2-(tert-butoxycarbonylamino)-4-phenylbutanoate (corresponding tocompound 86)

Starting from 2-(tert-butoxycarbonylamino)-4-phenylbutanoic acid and3-(bromomethyl)phenyl alcohol and following the procedure reported inExample 3 the title compound was obtained as an oil.

¹H-NMR (CDCl₃): 7.50-7.16 (7H, m); 7.15-7.05 (2H, m); 5.42 (2H, s); 5.07(1H, d); 4.65-4.47 (1H, m); 2.80 (2H, t); 2.44-2.23 (1H, m); 2.23-1.99(1H, m); 1.48 (9H, s).

EXAMPLE 21 2-(2-(Nitrooxy)ethoxy)ethyl2-(tert-butoxycarbonylamino)-4-phenylbutanoate

Starting from 2-(tert-butoxycarbonylamino)-4-phenylbutanoic acid and2-chloroethoxyethyl alcohol and following the procedure reported inExample 3 the title compound was obtained as an oil.

¹H-NMR (CDCl₃): 7.19-7.03 (5H, m); 5.08 (1H, d); 4.50-4.45 (2H, m);4.22-4.06 (3H, m); 3.65-3.55 (4H, m); 2.56 (2H, t); 2.08-1.80 (2H, m);1.32 (9H, s).

EXAMPLE 22

2,2-Dimethyl-14-(nitrooxy)-4,9-dioxo-3,8,10-trioxa-5-azatetradecane-6-carboxylicacid (corresponding to compound (401))

The title compound was prepared from N-Boc-L-serine and 4-chlorobutylchloroformate following procedure described in Example 16.

¹H-NMR (CDCl₃): 5.50 (1H, d); 4.52-4.40 (5H, m); 4.19 (2H, t); 1.88-1.75(4H, m); 1.46 (9H, s).

2-amino-3-((4-(nitrooxy)butoxy)carbonyloxy)propanoic acid hydrochloride(corresponding to compound (407))

The title compound was obtained as a white solid from2,2-dimethyl-14-(nitrooxy)-4,9-dioxo-3,8,10-trioxa-5-azatetradecane-6-carboxylicacid (described in Example 22) following procedure described in Example4.

¹H-NMR (DMSO-d₆): 4.60-4.41 (4H, m); 4.18-4.13 (3H, m); 1.78-1.65 (4H,m).

EXAMPLE 24

4-(nitrooxy)butyl2-(tert-butoxycarbonylamino)-3-(4-hydroxyphenyl)propanoate(corresponding to compound 67)

To a solution of Boc-(L)-tyrosine (5.0 g, 17.77 mmol) inN,N-dimethylformamide (40 ml) cesium carbonate (5.79 g, 17.77 mmol) wasadded. The reaction was cooled at 0° C. and a solution of 4-bromobutylnitrate (17.77 mmol) in dichloromethane (20% w/w, 17.06 g) was addeddrop wise. The reaction was stirred at 0° C. for 20 minutes and then atroom temperature for 22 hours. The mixture was poured into a 5% aqueousNaH₂PO₄ solution and extracted with diethyl ether (40×4 ml), the organiclayers were dried over sodium sulfate and concentrated under reducedpressure. The residue was purified by flash chromatography(n-hexane/EtOAc from 9:1 to 1:1 as eluent affording the title compound.

¹H-NMR (CDCl₃): 7.00 (2H, d, J=8 Hz); 6.76 (2H, d, J=8 Hz); 5.01 (1H,bd, J=8 Hz); 4.51 (1H, m); 4.42 (2H, t, J=6 Hz); 4.12 (2H, m); 3.00 (2H,d, J=6 Hz); 1.69 (4H, m); 1.44 (9H, s).

EXAMPLE 25 4-(nitrooxy)butyl 2-amino-3-(4-hydroxyphenyl)propanoate(corresponding to compound (58)

The title compound was obtained from 4-(nitrooxy)butyl2-(tert-butoxycarbonylamino)-3-(4-hydroxyphenyl)propanoate (described inExample 24) following procedure described in Example 4.

¹H-NMR (CDCl₃): 7.05 (2H, dd, J=9 and 3 Hz); 6.74 (2H, dd, J=9 and 3Hz); 4.45 (2H, t, J=6 Hz); 4.15 (2H, t, J=6 Hz); 3.73 (1H, m); 2.93 (2H,m); 1.73 (4H, m).

EXAMPLE 26

2-(R)-5,6-bis(nitrooxy)hexyl 1-tert-butyl pyrrolidine-1,2-dicarboxylate(corresponding to compound 4,5-(R)-isomer)

To a solution of N-Boc-L-Proline (288 mg, 1.34 mmol) and(2R)-6-hydroxypentane-1,2-diyl dinitrate (obtained as described inWO2005070868(A1)) (300 mg, 1.34 mmol) in CH₂Cl₂ (6 mL) was added at 0°C. EDAC (257 mg, 1.34 mmol), and then DMAP (catalytic). The reaction wasstirred overnight at rt. The organic layer was washed successively withH₂O, HCl 0.1M, H₂O and brine, dried over Na₂SO₄, filtered andevaporated. The residue was purified by column chromatography on silica(15% to 25% AcOEt in n-Hexane in 20 CV, then 25% to 35% in 5 CV) to givethe title compound (413 mg, 73%).

¹H NMR (300 MHz, CDCl₃) δ5.30 (m, 1H), 4.77 (m, 1H), 4.50 (m, 1H), 4.31(d, J=11.5 Hz, 1H), 4.19 (m, 2H), 3.47 (m, 2H), 1.94 (m, 3H), 1.76 (m,4H), 1.56 (m, 3H), 1.45 (d, J=12.67 Hz, 9H).

EXAMPLE 27

(R)-5,6-bis(nitrooxy)hexyl pyrrolidine-2-carboxylate (corresponding tocompound 1; 5(R)-isomer)

To a solution of [(5R)-5,6-dinitroxyloxane-1-yl] N-tButoxy-L-prolineester (410 mg, 0.97 mmol) in CH₂Cl₂ (3 mL) was added TFA (223 μL, 2.91mmol, 3 eq). The reaction was stirred at RT for 3 hrs. The organic layerwas washed with H₂O, K₂CO₃ diluted, H₂O and brine, dried over Na₂SO₄,filtered and evaporated yielding the title compound (215 mg, 69%).

¹H NMR (300 MHz, CDCl₃) δ5.31 (ddd, J=13.23, 6.51, 3.09 Hz, 1H), 4.77(dd, J=12.88, 3.07 Hz, 1H), 4.50 (dd, J=12.87, 6.46 Hz, 1H), 4.17 (t,J=6.30 Hz, 2H), 3.82 (dd, J=8.46, 5.25 Hz, 1H), 3.13 (dd, J=16.88, 6.54Hz, 1H), 2.42 (s, 2H), 2.17 (m, 1H), 1.78 (m, 6H), 1.52 (m, 3H).

EXAMPLE 28

2-(tert-butoxycarbonylamino)ethyl 4-(nitrooxy)butanoate (correspondingto compound (508)) Step A: 2-(tert-butoxycarbonylamino)ethyl4-bromobutanoate

N-Boc-ethanolamine (2.10 g; 13.0 mmol), 4-Bromobutyric acid (2.18 g;13.0 mmol) and N,N-dimethylaminopyridine (0.318 g; 2.60 mmol) weredissolved in CH₂Cl₂ (35 mL) and the mixture was cooled to 0° C.; EDAC(3.75 g; 19.6 mmol) was added and the reaction was slowly warmed to roomtemperature and stirred for 18 hours. Then the mixture was diluted withCH₂Cl₂, washed with aqueous Na₂HPO₄ (5%, 2×50 ml) aqueous NaH₂PO₄ (5%,2×50 ml) and brine (1×40 ml). The organic layer was dried over sodiumsulfate and concentrated under reduced pressure.

The residue was purified by flash chromatography (hexane/EtOAc=75/25;R_(f)=0.40), yielding the title compound (3.03 g, 75%).

Step B: 2-(tert-butoxycarbonylamino)ethyl 4-(nitrooxy)butanoate

To a solution of 2-(tert-butoxycarbonylamino)ethyl 4-bromobutanoate(3.03 g; 9.77 mmol) in CH₃CN (80 mL), AgNO₃ (4.15 g; 24.4 mmol) wasadded and the reaction was performed at the microwave (120° C., 7 min).The formed salts were filtered off and the solvent was concentrated;then the residue was diluted with EtOAc and washed with water (40 ml);the organic layer was dried over sodium sulfate and concentrated underreduced pressure.

The residue was purified by flash chromatography (hexane/EtOAc=7/3;R_(f)=0.40), yielding the title compound (1.48 g, 52%).

¹H-NMR (300 MHz, CDCl₃): 4.77 (1H, s); 4.54 (2H, t); 4.17 (2H, t);3.44-3.38 (2H, m); 2.49 (2H, t); 2.13-2.04 (2H, m); 1.46 (9H, s).

EXAMPLE 29

2-aminoethyl 4-(nitrooxy)butanoate hydrochloride (corresponding tocompound (509))

The title compound was obtained as a white solid starting from2-(tert-butoxycarbonylamino)ethyl 4-(nitrooxy)butanoate, prepared asdescribed in Example 28 following the procedure described in Example 4(1.16 g; quantitative yield).

¹H-NMR (DMSO-d₆): 8.25 (2H, s); 4.56 (2H, t); 4.23 (2H, t); 3.06 (2H,t); 2.51 (2H, t); 2.01-1.91 (2H, m).

EXAMPLE 30 (S)-2-(tert-butoxycarbonylamino)-3-phenylpropyl4-(nitrooxy)butanoate (corresponding to compound (511))

The title compound was prepared from (S)-tert-butyl1-hydroxy-3-phenylpropan-2-ylcarbamate and 4-Bromobutyric acid followingthe procedure described in Example 29.

¹H-NMR (300 MHz, CDCl₃): 7.35-7.25 (5H, m); 4.56-4.54 (1H, m); 4.52 (2H,t); 4.15-4.04 (3H, m); 2.84-2.81 (2H, m); 2.50 (2H, t); 2.13-2.04 (2H,m); 1.32 (9H, s).

EXAMPLE 31

(S)-4-(nitrooxy)butyl 2-(tert-butoxycarbonylamino)-3-phenylpropanoate(corresponding to compound (15))

The title compound was prepared from(S)-2-(tert-butoxycarbonylamino)-3-phenylpropanoic acid and4-chloro-1-butanol following the procedure described in Example 3.

¹H-NMR (300 MHz, CDCl₃): 7.31 (3H, m), 7.16 (2H, d), 4.98 (1H, bd), 4.56(1H, bm), 4.41 (2H, t), 4.12 (2H, m), 3.08 (2H, d), 1.69 (4H, m), 1.93(9H, s).

EXAMPLE 32

(S)-4-hydroxybutyl pyrrolidine-2-carboxylate

The title compound was prepared from Boc-Proline and 4-chloro-1-butanolfollowing the procedure described in Example 3, eventually hydrolyzingthe Boc protective group as described in Example 4.

¹H-NMR (CDCl₃): 4.5 (3H, m), 4.3 (2H, bt), 3.57 (2H, m), 2.45 (1H, m)2.13 (3H, m), 1.87 (4H, m).

EXAMPLE 33

((S)-bis(4-(nitrooxy)butyl) 2-(tert-butoxycarbonylamino)succinate(corresponding to compound (468))

The title compound was prepared from L-Boc-Aspartic acid and4-chloro-1-butanol following the procedure described in Example 3.¹H-NMR (CDCl₃): 5.48 (1H, bd), 4.58 (1H, bd), 4.51 (4H, t), 4.23 (2H,t), 2.93 (2H, m), 1.81 (8H, m), 1.47 (9H, s).

EXAMPLE 34

(S)—((R)-5,6-bis(nitrooxy)hexyl)2-(tert-butoxycarbonylamino)-3-phenylpropanoate (corresponding tocompound (123, 5(R)-isomer))

The title compound was prepared from Boc-L-Phenylalanine and(2R)-6-hydroxypentane-1,2-diyl dinitrate (obtained as described inWO2005070868(A1)) following the procedure described in Example 26.

EXAMPLE 35

(S)—((R)-5,6-bis(nitrooxy)hexyl) 2-amino-3-phenylpropanoate(corresponding to compound 14 5(R)-isomer)

The title compound was prepared from (S)—((R)-5,6-bis(nitrooxy)hexyl)2-(tert-butoxycarbonylamino)-3-phenylpropanoate (prepared as describedin Example 34) following procedure described in Example 4.

¹H-NMR (CDCl₃): 9.04-8.65 (2H, m), 7.47-7.14 (5H, m), 5.31-5.15 (1H, m),4.80-4.65 (1H, m) 4.55-4.31 (1H, m), 4.23-3.96 (2H, m); 3.60-3.42 (1H,m); 3.42-3.23 (1H, m); 1.74-1.46 (4H, m); 1.45-1.15 (2H, m).

EXAMPLE 35 4-[(nitrooxy)methyl]benzyl2-(tert-butoxycarbonylamino)acetate (corresponding to compound (87))

The title compound was prepared from N-Boc-Glycine N-hydroxysuccinimidoester and 4-(chloromethyl)benzyl alcohol following procedures reportedin Example 3.

¹H-NMR (CDCl₃): 7.41 (4H, s), 5.44 (2H, s), 5.19 (2H, s), 5.02 (1H, bs),3.97 (2H, d), 1.47 (9H, s).

EXAMPLE 36

4-[(nitrooxy)methyl]benzyl 2-aminoacetate (corresponding to compound(33))

The title compound was prepared from 4-[(nitrooxy)methyl]benzyl2-(tert-butoxycarbonylamino)acetate (prepared in Example 35) followingprocedures reported in Example 4.

¹H-NMR (CDCl₃): 8.66-8.34 (2H, m), 7.59-7.40 (4H, m), 5.59 (2H, s), 5.26(2H, s) 3.87 (2H, s).

EXAMPLE 37

(S)-bis(4-(nitrooxy)butyl) 2-(tert-butoxycarbonylamino)pentanedioate(corresponding to compound (472))

The title compound was prepared from L-Boc-Glutamic acid and4-chloro-1-butanol following the procedure described in Example 3,eventually hydrolyzing the Boc protective group as described in Example4.

¹H-NMR (CDCl₃): 5.28 (1H, bd), 4.48 (1H, bd), 4.19 (2H, t), 4.07 (2H,t), 2.40 (3H, m), 2.03 (1H, m), 1.72 (8H, m), 1.45 (9H, s).

EXAMPLE 38

(S)-4-(nitrooxy)butyl 2-amino-3-phenylpropanoate (corresponding tocompound (40))

The title compound was prepared from (S)-4-(nitrooxy)butyl2-(tert-butoxycarbonylamino)-3-phenylpropanoate (prepared as describedin Example 31) following procedure described in Example 4.

¹H-NMR (DMSO): 8.7 (3H, bs), 7.30 (5H, m), 4.47 (2H, d), 4.25 (1H, t),4.08 (2H, t), 3.15 (2H, m), 1.54 (4H, m).

PHARMACOLOGICAL EXAMPLE

The ability of the compounds of the present invention to release nitricoxide was assessed testing their vasorelaxant activity in isolatedrabbit thoracic aorta preparations (Wanstall J. C. et al., Br. J.Pharmacol., 134:463-472, 2001).

The compounds of the invention that were tested are the compounds of thefollowing formulas: 7, 8, 9, 12, 13, 15, 86, 87, 123, 407, 508, 511;

and compounds reported in Examples 14, 15, and 21.

Method

Male New Zealand rabbits were anaesthetized with thiopental-Na (50mg/kg, iv), sacrificed by exsanguinations and then the thorax was openedand the aorta dissected. Single ring preparations (4 mm in length) ofthoracic aorta were set up in physiological salt solution (PSS) at 37°C. in small organ chambers (5 ml). The composition of PSS was (mM): NaCl130, NaHCO₃ 14.9, KH₂PO₄ 1.2, MgSO₄ 1.2, HEPES 10, CaCl₂, ascorbic acid170 and glucose 1.1 (95% O₂/5% CO₂; pH 7.4). Each ring was mounted under2 g passive tension in 5 ml organ bath. Isometric tension was recordedwith a Grass transducer (Grass FT03) attached to a BIOPAC MP150 System.Preparations were allowed to equilibrate for 1 h, then contractedsubmaximally with noradrenaline (NA, 1 μM) and, when the contraction wasstable, acetylcholine (ACh, 10 μM) was added. A relaxant response to AChindicated the presence of a functional endothelium. When a stableprecontraction was reached, a cumulative concentration-response curve toeither of the vasorelaxant agents was obtained in the presence of afunctional endothelium. Time intervals between different concentrationswere based on the time needed to reach a full response.

Moreover, the nitric oxide-dependent vascular relaxation elicited by thetested compounds was examined preincubating the aortic rings with thesoluble guanylyl cyclase inhibitor ODQ(1-H-(1,2,4)-oxadiazol(4,3-a)quinoxalin-1-one) at 10 μM for 20 min.Responses to vasorelaxing agents were measured from the plateau of NAcontraction. The IC₅₀ (concentration giving 50% reversal of NAcontraction) was interpolated from the plots of relaxant-response vs logmolar concentration of tested compound.

During the experimental period, the plateau obtained with NA was stablewithout significant spontaneous loss of contraction in the aortic rings.

As shown in the following Table 1, the compounds of the invention wereable to induce relaxation in a concentration-dependent manner.Furthermore, in experiments performed in the presence of ODQ (10 μM),the vascular relaxation of the tested compounds was inhibited.

TABLE 1 Compound IC₅₀ (μM) ± sem Example 15  1.2 ± 0.33 Example 14 1.9 ±0.4 Compound 8 2.6 ± 0.6 Compound 7 2.4 ± 0.5 Compound 9 4.5 ± 1.4Compound 86 5.2 ± 0.9 Compound 13 10.2 ± 0.5  Example 21 8.0 ± 1.8Compound 87 2.1 ± 0.4 Compound 12 10.2 ± 4.2  Compound 508 4.4 ± 0.7Compound 15 12.6 ± 6.4  Compound 511 9.5 ± 3.6 Compound 123 0.64 ± 0.14Compound 407  16 ± 6.4 IC₅₀ is the concentration which inhibits 50% ofthe response.

1. A compound of formula (I) and pharmaceutically acceptable salts orstereoisomers thereof:

wherein s is 1, s′ and s″ are independently selected from 0 or 1, m, m′and m″ are each independently selected from 0 or 1 with the proviso thatwhen m, m′ or m″ are 0, A is linked directly to the groups —(Y—ONO₂),—(Y′—ONO₂), —(Y″—ONO₂), B at each occurrence is independently selectedfrom:

A is a radical selected from the group consisting of:

wherein in formulas (IIa)-(IIm) and (IIo)-(IIu), R₁ is selected from: H,—C(O)O—C(CH₃)₃, —C(O)—R_(n), —C(O)O—R_(1x), wherein R_(1x) is one of thegroups —[(B)_(m)—(Y—ONO₂)]_(s), —[(B)_(m′)—(Y′—ONO₂)]_(s′) or—[(B)_(m″)—(Y″—ONO₂)]_(s″) of formula (I) wherein m, m′ and m″ are 0 andY, Y′ and Y″ are as below reported; in formulas (IIa)-(IIu) R₂ isselected from: —C(O)OH, —C(O)—OC(CH₃)₃, —C(O)OR_(2x), —C(O)NHR_(2xx),—C(O)N(CH₃)R_(2xx) wherein R_(2x) and R_(2xx) are one of the groups—[(B)_(m)—(Y—ONO₂)]_(s), —[(B)_(m′)—(Y′—ONO₂)]_(s′) or—[(B)_(m″)—(Y″—ONO₂)]_(s″) of formula (I) wherein m, m′ and m″ are 0 or1, B is as above defined and Y, Y′ and Y″ are as below reported, R_(2xx)is one of the groups —[(B)_(m)—(Y—ONO₂)]_(s), —[(B)_(m′)—(Y′—ONO₂)]_(s′)or —[(B)_(m″)—(Y″—ONO₂)]_(s″) of formula (I) wherein m, m′ and m″ are 0and Y, Y′ and Y″ are as below reported, or R₂ is the group R₄:

in formula (IIa), R_(a) is selected from the groups consisting of: a)—H, —CH₃, isopropyl, isobutyl, sec-butyl, tert-butyl,methylthio-(CH₂)₂—, phenyl, benzyl, C₆H₅—CH₂—CH₂—, 2-monosubstitutedbenzyl, or 3-monosubstituted benzyl or 4-monosubstituted benzyl withgroups such as —F, —Cl, I, —NO₂, —CF₃, —CH₃, CN, C₆H₅CO—; or R_(a) is2,4-dichlorobenzyl, 3,4-dichlorobenzyl, 3,4-difluorobenzyl,3-triptophanyl-CH₂—, 3-benzothienyl-CH₂—, 4-imidazolyl-CH₂—,9-anthranyl-CH₂—, cyclohexyl, cyclohexyl-CH₂—, cyclohexyl-(CH₂)₂—,cyclopentyl-CH₂—, (C₆H₅)₂CH—, 4-quinolyl-CH₂—, 3-quinolyl-CH₂—,2-quinolyl-CH₂—, 2-quinoxalyl-CH₂—, 2-furyl-CH₂—, 1-naphtyl-CH₂—,2-naphtyl-CH₂—, 2-pyridyl-CF₁₂—, 3-pyridyl-CH₂—, 4-pyridyl-CH₂—,2-thienyl-CH₂—, 3-thienyl-CH₂—, C₆H₄—CH═CH—CH₂—, CH≡CH—CH₂—,NH₂—CO—CH₂—, NH₂—CO—(CH₂)₂—, or —P(═O)(OCH₃)₂; b) HS—CH₂—,R_(bx)—C(O)—S—CH₂—, R_(bx)—OC(O)—S—CH₂—, R_(bx)—NH—C(O)S—CH₂— whereinR^(bx) is one of the groups —[(B)_(m)—(Y—ONO₂)]_(s),—[(B)_(m′)—(Y—ONO₂)]_(s′) or —[(B)_(m″)—(Y″—ONO₂)]_(s)″ of formula (I)wherein m, m′ and m″ are 0 and Y, Y′ and Y″ are as below defined; c)R_(x)O—CH₂—, R_(x)O—CH(CH₃)—, (R_(x)O)-p-C₆H₄—CH₂—,4-(R_(x)O)-3,5-diiodobenzyl-, 4-(R_(x)O)-3-nitrobenzyl- wherein R_(x) isH, R_(xx)—C(O)—, R_(xx)—OC(O)—, R_(xx)—NHC(O)— wherein R_(xx) is one ofthe groups —[(B)_(m)—(Y—ONO₂)]_(s), —[(B)_(m′)—(Y′—ONO₂)]_(s′) or—[(B)_(m″)—(Y″—ONO₂)]_(s″) of formula (I) wherein m, m′ and m″ are 0 andY, Y′ and Y″ are as below defined; d) R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂—,R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—, wherein R_(g) is OH, (CH₃)₃CO—,R_(gx)—O—, R_(g)—NH—, R_(g)—N(CH₃)— wherein R_(gx) is one of the groups—[(B)_(m)—(Y—ONO₂)]_(s), —[(B)_(m′)—(Y′—ONO₂)]_(s′) or—[(B)_(m″)—Y″—ONO₂)]_(s″) of formula (I) wherein m, m′ and m″ are 0 or1, B is as above defined and Y, Y′ and Y″ are as below reported, R_(gxx)is one of the groups —[(B)_(m)—(Y—ONO₂)]_(s), —[(B)_(m′),—(Y′—ONO₂)]_(s′) or —[(B)_(m″)—(Y″—ONO₂)]_(s″) of formula (I) wherein m,m′ and m″ are 0 and Y, Y′ and Y″ are as below reported, or R_(g) is thegroup R_(gg):

e) R_(h)NH(CH₂)_(p)— or R_(i)NH(═NH)NH—(CH₂)₃—, wherein p is an integerfrom 0 to 4, R_(h) is H, (CH₃)₃C—OC(O)—, R_(hh)—C(O)— or R_(hh)—OC(O)—,R_(i) is H, R_(ii)—C(O)— or R_(ii)—OC(O)—, wherein R_(hh) and R_(ii) areeach independently one of the groups —[(B)_(m)—(Y—ONO₂)]_(s),—[(B)_(m′)—(Y′—ONO₂)]_(s′ or —[(B)) _(m″)—(Y″—ONO₂)]_(s″) of formula (I)wherein m, m′ and m″ are 0 and Y, Y′ and Y″ are as below defined; informula (IIc) R_(c) is selected from the following groups: a′) H, CH₃,isopropyl, isobutyl, sec-butyl, methylthio-(CH₂)₂, phenyl, benzyl,biphenyl-CH₂, 3-triptophanyl-CH₂, NH₂—CO—CH₂, NH₂—CO—(CH₂)₂—; b′)HS—CH₂—, R_(bx)—C(O)—S—CH₂—, R_(bx)—OC(O)—S—CH₂—, R_(bx)—NH—C(O)S—CH₂—wherein R_(bx) is one of the groups —[(B)_(m)—(Y—ONO₂)]_(s),—[(B)_(m′)—(Y′—ONO₂)]_(s′) or —[(B)_(m″)—(Y″—ONO₂)]_(s)″ of formula (I)wherein m, m′ and m″ are 0 and Y, Y′ and Y″ are as below defined; c′)R_(x)O—CH₂—, R_(x)O—CH(CH₃)—, R_(x)O—C₆H₄—CH₂— wherein R_(x) is H,R_(xx)—C(O)—, R_(xx)—OC(O)—, R_(xx)—NHC(O)— wherein R_(xx) is one of thegroups —[(B)_(m)—(Y—ONO₂)]_(s), —[(B′)_(m′)—(Y′—ONO₂)]_(s′) or—[(B″)_(m″)—(Y″—ONO₂)]_(s″) of formula (I) wherein m, m′ and m″ are 0and Y, Y′ and Y″ are as below defined; d′) R_(g)C(O)CH₂—,R_(g)C(O)(CH₂)₂— wherein R_(g) is OH, (CH₃)₃CO—, R_(gx)—O—, R_(gxx)—NH—,R_(gxx)—N(CH₃)— wherein R_(gx) is one of the groups—[(B)_(m)—(Y—ONO₂)]_(s), —[(B)_(m′)—(Y′—ONO₂)]_(s′) or—[(B)_(m″)—(Y″—ONO₂)]_(s″) of formula (I) wherein m, m′ and m″ are 0 or1, B is as above defined and Y, Y′ and Y″ are as below reported, R_(gxx)is one of the groups —[(B)_(m′)—(Y—ONO₂)]_(s′),—[(B)_(m′)—(Y′—ONO₂)]_(s′) or —[(B)_(m″)—(Y″—ONO₂)]_(s″) of formula (I)wherein m, m′ and m″ are 0 and Y, Y′ and Y″ are as below reported; e′)R_(h)NH(CH₂)_(p)— or R_(i)NH(═NH)NH—(CH₂)₃—, wherein p is an integerfrom 0 to 4, R_(h) is H, —C(O)O—C(CH₃)₃, R_(hh)—C(O)— or R_(hh)—OC(O)—,R_(i) is H, R_(ii)—C(O)— or R_(ii)—OC(O)—, wherein R_(hh) and R_(ii) areeach independently one of the groups —[(B)_(m)—(Y—ONO₂)]_(s),—[(B)_(m′)—(Y″—ONO₂)]_(s′) or —[(B)_(m″)-(Y″—ONO₂)]_(s″) of formula (I)wherein m, m′ and m″ are 0 and Y, Y′ and Y″ are as below defined; informula (IIl) Ph is phenyl, a′ is equal to 0, 1, 2, or 3; and a is equalto 0 or 1 with the proviso that a is 0 or 1 when a′ is 0 and a is 0 whena′ is 1, 2 or 3; in formula (IIi) the group R₂ can be attached to one ofthe positions 1, 2 or 3 of the cyclohexyl ring; in formulae (IIj) and(IIk) the symbol

represents a single bond or a double bond; in formula (IIk) the group R₂can be attached to one of the positions 1, 2 or 3 of the piperidyl ring;in formula (IIl), R_(L) is selected from: H, methyl, propyl, allyl,(C₆H₅)₂CH—, 1-naphtyl-CH₂—, benzyl, 2-bromobenzyl, 2-chlorobenzyl,3-chlorobenzyl, 4-fluorobenzyl, 4-bromobenzyl, 4-methylbenzyl; informula (IIm) R_(m) is selected from: benzyl, 2-bromobenzyl,4-bromobenzyl, 4-methylbenzyl; in formula (IIn) R_(n) is selected from:—H, —C(O)—R_(nx), —C(O)O—R_(nx) or —(CH₂)₂—NH—R_(h) wherein R_(h) is —H,—C(O)O—C(CH₃)₃, —C(O)—R_(hh), —C(O)O—R_(hh) wherein R_(nx) and R_(hh)are each independently one of the groups —[(B)_(m)—(Y—ONO₂)]_(s),—[(B)_(m′)—(Y′—ONO₂)]_(s′) or —[(B)_(m″)—(Y″—ONO₂)]_(s″) of formula (I)wherein m, m′ and m″ are 0 and Y, Y′ and Y″ are as below defined; informula (IIp), c is 0 or 1 and R₂ can be attached to the position 1, 2or 3 of the phenyl ring; in formula (IIs), R₃ is selected from: OH,—OC(O)—R_(3x), —OC(O)O—R_(3x), —OC(O)—NH—R_(3x) wherein R_(3x) is one ofthe groups —[(B)_(m)—(Y—ONO₂)]_(s), —[(B)_(m′)—(Y′—ONO₂)]_(s′) or—[(B)_(m″)—(Y″—ONO₂)]_(s″) of formula (I) wherein m, m′ and m″ are 0 andY, Y′ and Y″ are as below defined; in formula (IIs) R_(s) is selectedfrom the following groups: a″) —H, —CH₃, isopropyl, isobutyl, sec-butyl,tert-butyl, methylthio-(CH₂)₂—, benzyl, 2-monosubstituted benzyl, or3-monosubstituted benzyl, 3-triptophanyl-CH₂—, 4-imidazolyl-CH₂—,NH₂—CO—CH₂—, NH₂—CO—(CH₂)₂—; b″) HS—CH₂—, R_(bx)—C(O)—S—CH₂—,R_(bx)—OC(O)—S—CH₂—, R_(bx)—NH—C(O)S—CH₂— wherein R_(bx) is one of thegroups —[(B)_(m)—(Y—ONO₂)]_(s), —[(B)_(m′)—(Y′—ONO₂)]_(s′) or—[(B)_(m″)—(Y″—ONO₂)]_(s″) of formula (I) wherein m, m′ and m″ are 0 andY, Y′ and Y″ are as below defined; c″) R_(x)O—CH₂—, R_(x)O—CH(CH₃)—,(R_(x)O)-p-C₆H₄—CH₂—, 4-(R_(x)O)-3,5-diiodobenzyl-,4-(R_(x)O)-3-nitrobenzyl- wherein R_(x) is H, R_(xx)—C(O)—,R_(xx)—OC(O)—, R_(xx)—NHC(O)— wherein R_(xx) is one of the groups—[(B)_(m)—(Y—ONO₂)]_(s), —[(B)_(m′)—(Y′—ONO₂)]_(s′) or—[(B)_(m″)—(Y″—ONO₂)]_(s″) of formula (I) wherein m, m′ and m″ are 0 andY, Y′ and Y″ are as below defined; d″) R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂,R_(g)C(O)(CH₂)₂—, R_(g)C(O)(CH₂)₄—, wherein R_(g) is OH, (CH₃)₃CO—,R_(gx)—O—, R_(g)—NH—, R_(g)—N(CH₃)— wherein R_(gx) is one of the groups—[(B)_(m)—(Y—ONO₂)]_(s), —[(B)_(m′)—(Y′—ONO₂)]_(s′) or—[(B)_(m″)—(Y″—ONO₂)]_(s″) of formula (I) wherein m, m′ and m″ are 0 or1, B is as above defined and Y, Y′ and Y″ are as below reported, R_(gxx)is one of the groups —[(B)_(m)—(Y—ONO₂)]_(s), —[(B)_(m′)—(Y′—ONO₂)]_(s′)or —[(B)_(m″)—(Y″—ONO₂)]_(s″) of formula (I) wherein m, m′ and m″ are 0and Y, Y′ and Y″ are as below reported, e″) R_(h)NH(CH₂)_(p)— orR_(i)NH(═NH)NH—(CH₂)₃—, wherein p is an integer from 0 to 4, R_(h) is H,(CH₃)₃C—OC(O)—, R_(hh)—C(O)— or R_(hh)—OC(O)—, R_(i) is H, R_(ii)—C(O)—or R_(ii)—OC(O)—, wherein R_(hh) and R_(ii) are each independently oneof the groups —[(B)_(m)—(Y—ONO₂)]_(s), —[(B)_(m′)—(Y′—ONO₂)]_(s′) or—[(B)_(m″)—(Y″—ONO₂)]_(s″) of formula (I) wherein m, m′ and m″ are 0 andY, Y′ and Y″ are as below defined; in formula (IIt) d is an integer from2 to 5, d′ is 0 or 1, with the proviso that d′ is 0 when d is an integerfrom 3 to 5, R_(t) is H, —C(O)—R_(tt) or —C(O)O—R_(tt) wherein R_(tt) isone of the groups —[(B)_(m)—(Y—ONO₂)]_(s), —[(B′)_(m′)—(Y′—ONO₂)]_(s′)or —[(B″)_(m″)—(Y″—ONO₂)]_(s″) of formula (I) wherein m, m′ and m″ are0; in formula (IIu) a and b are each independently 0 or 1, R_(x) is H,—C(O)—R_(xx), —C(O)O—R_(xx)—, —C(O)NH—R_(xx) wherein R_(xx) is one ofthe groups —[(B)_(m)—(Y—ONO₂)]_(s), —[(B)_(m′)—(Y′—ONO₂)]_(s′) or—[(B)_(m″)—(Y″—ONO₂)]_(s″) of formula (I) wherein m, m′ and m″ are 0 andY, Y′ and Y″ are as below defined; Y, Y′ and Y″ of the groups (Y—ONO₂),—(Y′—ONO₂) and —(Y″—ONO₂) of formula (I) are bivalent radicals and theyare each independently selected from: A) a straight or branched C₁-C₂₀alkylene, a straight or branched C₁-C₂₀ alkylene substituted with one ormore —ONO₂ group(s); a cycloalkylene having 5 to 7 carbon atoms, thering being optionally substituted with a straight or branched C₁-C₁₀alkyl; B)

wherein n⁰ is an integer from 0 to 20, n¹ is an integer from 1 to 20,wherein in formulas (IB) and (IB′) the —ONO₂ group is linked to C)

wherein: n is an integer from 1 to 20, n₂ is an integer from 0 to 2, R²is H or CH₃, X₁ is —OC(O)— or —C(O)O—; wherein in formula (IC) the —ONO₂group is linked to —(CH₂)_(n) ¹—; D)

wherein in formula (ID): n¹ is an integer from 1 to 20, n², R² and X₁are as defined above; Y¹ is —CH₂—CH₂— or —CH═CH—(CH₂)_(n) ^(2a)— whereinn^(2a) is an integer from 0 to 5, wherein in formula (ID) the —ONO₂group is linked to —(CH₂)_(n) ¹—; E)

wherein X₂ is —O—, —S—, —NH— or —N(CH₂CH₂OCH₃)—, n³ is an integer from 1to 5, n₃ is an integer from 0 to 10, n₄ an integer from 1 to 10, n_(3′)is an integer from 0 to 10, n_(4′) an integer from 1 to 10, R² is H or—CH₃, wherein in formula (IE) the —ONO₂ group is linked to the—(CH₂)_(n4′) group; F)

wherein: n⁵ is an integer from 0 to 10; n⁶ is an integer from 1 to 10;R⁴, R⁵, R⁶, R⁷ are the same or different, and are H or straight orbranched C₁-C₄ alkyl, wherein in formula (IF) the —ONO₂ group is linkedto

wherein n⁶ is as defined above; Y² is an heterocyclic saturated,unsaturated or aromatic 5 or 6 members ring, containing one or moreheteroatoms selected from nitrogen, oxygen, sulfur, and is selected fromthe group consisting of:

G)

wherein n⁰ is an integer from 0 to 10, n⁷ is an integer from 1 to 10, n⁸is an integer from 0 to 10, R⁸ is CH₃ or CH₂ONO₂, wherein in formula(IG) the —ONO₂ group is linked to the group

with the proviso that in formula (I) s′ and s″ cannot be both 1 when: Ais the radical of formulas (IIb), (IId)-(IIr), or A is the radical offormula (IIt) wherein d is from 3 to 5 and d′ is 0, or A is the radicalof formula (IIu) wherein a is 0; with the proviso that s′ and s″ can beboth 1 when: A is the radical of formulas (IIa), (IIc) or (IIs) andR_(a), R_(c) and R_(s) are selected from R_(bx)—C(O)—S—CH₂—,R_(bx)—OC(O)—S—CH₂—, R_(bx)—NH—C(O)S—CH₂— wherein R_(bx) is one of thegroups —[(B)_(m)—(Y—ONO₂)]_(s), —[(B)_(m′)—(Y′—ONO₂)]_(s′) or—[(B)_(m″)—(Y″—ONO₂)]_(s″) wherein m, m′ and m″, B, Y, Y′ and Y″ are asabove defined; R_(x)O—CH₂—, R_(x)O—CH(CH₃)—, (R_(x)O)-p-—C₆H₄—CH₂—,4-(R_(x)O)-3,5-diiodobenzyl-, 4-(R_(x)O)-3-nitrobenzyl- wherein R_(x) isR_(xx)—C(O)—, R_(xx)—OC(O)— or R_(xx)—NHC(O)— wherein R_(xx) is one ofthe groups —[(B)_(m)—(Y—ONO₂)]_(s), —[(B)_(m′)—(Y′—ONO₂)]_(s′) or—[(B)_(m″)—(Y″—ONO₂)]_(s″) wherein m, m′ and m″, B, Y, Y′ and Y″ are asabove defined; R_(g)C(O)CH₂—NH—, R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—,R_(g)C(O)(CH₂)₄—, wherein R_(g) is OH, (CH₃)₃CO—, R_(gx)—O—,R_(gxx)—NH—, R_(gxx)—N(CH₃)— wherein R_(gx) and R_(gxx) are one of thegroups —[(B)_(m)—(Y—ONO₂)]_(s), —[(B)_(m′)—(Y′—ONO₂)]_(s′) or—[(B)_(m″)—(Y″—ONO₂)]_(s″) wherein m, m′ and m″, B, Y, Y′ and Y″ are asabove defined; R_(h)NH(CH₂)_(p)— or R_(i)NH(═NH)NH—(CF₂)₃—, wherein p isan integer from 0 to 4, R_(h) is R_(hh)—C(O)— or R_(hh)—OC(O)—, R_(i) isR_(ii)—C(O)— or R_(ii)—OC(O)—, wherein R_(hh) and R_(ii) are one of thegroups —[(B)_(m)—(Y—ONO₂)]_(s), —[(B)_(m′)—(Y′—ONO₂)]_(s′) or—[(B)_(m″)—(Y″—ONO₂)]_(s″) wherein m, m′ and m″, B, Y, Y′ and Y″ are asabove defined; A is the radical of formula (IIt) wherein d′ is 1 and dis 2 and R_(t) is —C(O)—R_(tt) or —C(O)O—R_(tt) wherein R_(tt) is one ofthe groups —[(B), —(Y—ONO₂)]_(s), —[(B)_(m′)—(Y′—ONO₂)]_(s′) or—[(B)_(m″)—(Y″—ONO₂)]_(s″) wherein m, m′ and m″, B, Y, Y′ and Y″ are asabove defined; A is the radical of formula (IIu) wherein a is 1 andR_(x) is C(O)—R_(xx), —C(O)O—R_(xx) or —C(O)NH—R_(xx) wherein R_(xx) isone of the groups —[(B)_(m)—(Y—ONO₂)]_(s), —[(B)_(m′)—(Y′—ONO₂)]_(s′) or—[(B)_(m″)—(Y″—ONO₂)]_(s″) of formula (I) wherein m, m′ and m″ B, Y, Y′and Y″ are as above defined with the proviso that the followingcompounds of formula (I) are excluded: 3-(nitrooxy)propyl2-(tert-butoxycarbonylamino)-4-phenyl butanoate, 3-(nitrooxy)propyl2-amino-4-phenylbutanoate, 3-(nitrooxy)propyl 2-amino-4-phenylbutanoatehydrochloride, 4-(nitrooxy)butyl2-(tert-butoxycarbonylamino)-4-phenylbutanoate, 4-(nitrooxy)butyl2-amino-4-phenylbutanoate, 4-(nitrooxy)butyl 2-amino-4-phenylbutanoatehydrochloride, (2-(nitrooxy)ethoxy)methyl2-(tert-butoxycarbonylamino)-4-phenyl butanoate,(2-(nitrooxy)ethoxy)methyl 2-amino-4-phenylbutanoate,(2-(nitrooxy)ethoxy)methyl 2-amino-4-phenylbutanoate hydrochloride,1-tert-butyl 2-(4-(nitrooxy)butyl)pyrrolidine-1,2-dicarboxylate,4-(nitrooxy)butyl pyrrolidine-2-carboxylate, 4-(nitrooxy)butylpyrrolidine-2-carboxylate hydrochloride, 1-tert-butyl2-(3-(nitrooxy)propyl)pyrrolidine-1,2-dicarboxylate, 3-(nitrooxy)propylpyrrolidine-2-carboxylate 3-(nitrooxy)propyl pyrrolidine-2-carboxylateHydrochloride.
 2. The compounds according to claim 1 wherein in formula(I) Y, Y′ and Y″ of the groups (Y—ONO₂), —(Y′—ONO₂) or —(Y″—ONO₂) areeach independently selected from: A) a straight or branched C₂-C₁₀alkylene a straight or branched C₂-C₁₀ alkylene substituted with a —ONO₂group; E)

wherein in formula (IE) n³ is from 1 to 5 n₃ is 0 and n₄ is from 1 to 4,n_(3′) is 0 and n_(4′) is from 1 to 4, X₂ is or —NH—, R² is H.
 3. Thecompounds according to claim 1 wherein in formula (I) Y, Y′ and Y″ ofthe groups (Y—ONO₂), —(Y′—ONO₂) or —(Y″—ONO₂) are each independentlyselected from: B)

wherein in formula (IB) n⁰ is from 0 to 5 and n¹ is an integer from 1 to10; C)

wherein in formula (IC) n¹ is an integer from 1 to 10, n² is 1 and R² isCH₃, X₁ is —C(O)O—; D)

wherein in formula (ID): n² is 1 and R² is CH₃, Y¹ is —CH═CH—(CH₂)_(n)^(2a)— wherein n^(2a) is 0, X₁ is —C(O)O— and n¹ is an integer from 1 to10;
 4. The compounds according to claim wherein in formula (I) s is 1and m is 0, s′ and s″ are 0, A is selected from:

wherein R₁ is H or —C(O)—OC(CH₃)₃, R₂ is —C(O)OR_(2x), —C(O)NHR_(2xx),—C(O)N(CH₃)R_(2xx) wherein R_(2x) and R_(2xx) are the group —(Y—ONO₂),R_(a) of formula (ha) is selected from: a) H, CH₃, isopropyl, isobutyl,sec-butyl, methylthio-(CH₂)₂—, benzyl, C₆H₅—CH₂—CH₂—,3-triptophanyl-CH₂—, NH₂—CO—CH₂—, NH₂—CO—(CH₂)₂—, 4-imidazolyl-CH₂—; b)HS—CH₂—, c) R_(x)O—CH₂—, R_(x)O—CH(CH₃)—, (R_(x)O)-p-—C₆H₄—CH₂—, whereinR_(x) is H, d) R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—, wherein R_(g) is OH,(CH₃)₃CO—, or the group R_(gg):

e) R_(h)NH(CH₂)_(p)— or R_(i)NH(═NH)NH—(CH₂)₃—, wherein p is an integerequal to 3 or 4, R_(h) is H or (CH₃)₃C—OC(O)—, R_(i) is H; R_(c) offormula (IIc) is selected from the group comprising: H, CH₃, isopropyl,isobutyl, sec-butyl, methylthio-(CH₂)₂—, benzyl, 3-triptophanyl-CH₂,4-imidazolyl-CH₂—, NH₂—CO—CH₂—, NH₂—CO—(CH₂)₂—; R_(L) of formula (IIl)is H.
 5. The compounds according to claim 1 wherein in formula (I) s is1 and m is 0, s′ and s″ are 0, A is a radical selected from

wherein R₁ is —C(O)R_(1x), —C(O)OR_(1x) wherein R_(1x) is the group—(Y—ONO₂), R₂ in formulas (IIa) (He) and (IIl) is —C(O)OH,—C(O)—OC(CH₃)₃ or R₂ is the group R₄:

R₃ in formula (IIs) is OH; R_(a) of formula (ha) is selected from: a) H,CH₃, isopropyl, isobutyl, sec-butyl, methylthio-(CH₂)₂—, benzyl,C₆H₅—CH₂—CH₂—, 3-triptophanyl-CH₂—, NH₂—CO—CH₂—, NH₂—CO—(CH₂)₂—,4-imidazolyl-CH₂—; b) HS—CH₂—; c) R_(x)O—CH₂—, R_(x)O—CH(CH₃)—,(R_(x)O)-p-C₆H₄—CH₂— wherein R_(x) is H; d) R_(g)C(O)CH₂ orR_(g)C(O)(CH₂)₂—, wherein R_(g) is OH or (CH₃)₃C—O—, or R_(g) is thegroup R_(gg):

e) R_(h)NH(CH₂)_(p)— or R_(i)NH(═NH)NH—(CH₂)₃—, wherein p is an integerequal to 3 or 4, R_(h) is H or (CH₃)₃C—OC(O)—, R_(i) is H; R_(c) offormula (IIc) is selected from: H, CH₃, isopropyl, isobutyl, sec-butyl,methylthio-(CH₂)₂—, benzyl, 3-triptophanyl-CH₂—, 4-imidazolyl-CH₂—,NH₂—CO—CH₂—, NH₂—CO—(CH₂)₂—; R_(L) of formula (IIl) is H; R_(s) offormula (IIs) is H, CH₃, isopropyl, isobutyl, sec-butyl,methylthio-(CH₂)₂, benzyl, triptophanyl-CH₂, 4-imidazolyl-CH₂—,NH₂—CO—CH₂—, NH₂—CO—(CH₂)₂—;
 6. The compounds according to claim 1wherein in formula (I) s is 1 and m is 0, s′ and s″ are 0, A is aradical of formula (IIa) or (IIl)

wherein R₁ is —C(O)R_(1x) or —C(O)OR_(1x) wherein R_(1x) is the group—(Y—ONO₂), R₂ in formulas (IIa) and (IIl) is the group R₄:

R_(a) of formula (IIa) is selected from: a) H, CH₃, isopropyl, isobutyl,sec-butyl, methylthio-(CH₂)₂—, benzyl, C₆H₅—CH₂—CH₂—,3-triptophanyl-CH₂—, NH₂—CO—CH₂—, NH₂—CO—(CH₂)₂—, 4-imidazolyl-CH₂—; b)HS—CH₂—; c) R_(x)O—CH₂—, R_(x)O—CH(CH₃)—, (R_(x)O)-p-C₆H₄—CH₂—, whereinR_(x) is H; d) R_(g)C(O)CH₂ or R_(g)C(O)(CH₂)₂—, wherein R_(g) is OH orthe group R_(gg):

e) R_(h)NH(CH₂)_(p)— or R_(i)NH(═NH)NH—(CH₂)₃—, wherein p is an integerequal to 3 or 4, R_(h) is H or (CH₃)₃C—OC(O)—, R_(i) is H; R_(L) offormula (IIl) is H.
 7. The compounds according to claim 1 wherein informula (I) s is 1 and m is 0, s′ and s″ are 0, A is a radical offormula

wherein R₁ is H or —C(O)O—C(CH₃)₃, R₂ is —C(O)OH or R₂ is equal to thegroup R₄

R_(a) is selected from: b) R_(bx)C(O)—S—CH₂—, R_(bx)OC(O)—S—CH₂—,R_(bx)NH—C(O)S—CH₂— wherein R_(bx) is the group —(Y—ONO₂), c)R_(x)O—CH₂—, R_(x)O—CH(CH₃)—, (R_(x)O)-p-C₆H₄—CH₂—, wherein R_(x) isR_(xx)C(O)—, R_(xx)OC(O)— or R_(xx)NHC(O)— wherein R_(xx) is the group—(Y—ONO₂); d) R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂— wherein R_(g) is R_(gx)O—,R_(gxx)—NH—, or R_(gxx)—N(CH₃)—, wherein R_(gx) and R_(gxx) are thegroup —(Y—ONO₂); e) R_(h)NH(CH₂)_(p)— wherein p is 3 or 4, and R_(h) isR_(hh)C(O)— or R_(hh)OC(O)— wherein R_(hh) is the group —(Y—ONO₂); orR_(i)NH(═NH)NH—(CH₂)₃— wherein R_(i) is R_(ii)C(O)— or R_(ii)OC(O)—wherein R_(ii) is the group —(Y—ONO₂).
 8. The compounds according toclaim 1 wherein in formula (I) s is 1, m is 0, s′ and s″ are 0, A is aradical of formula

wherein R₁ is H or —C(O)—OC(CH₃)₃; R₃ is —OC(O)R_(3x), OC(O)OR_(3x),—OC(O)—NHR_(3x), wherein R_(3x) is the group —(Y—ONO₂); R_(s) isselected from: a″) H, CH₃, isopropyl, isobutyl, sec-butyl,methylthio-(CH₂)₂—, benzyl, C₆H₅—CH₂—CH₂—, 3-triptophanyl-CH₂—,NH₂—CO—CH₂, NH₂—CO—(CH₂)₂—, 4-imidazolyl-CH₂—.
 9. The compoundsaccording to claim 1 wherein in formula (I) s is 1 and m is 0, s′ and s″are 0, A is a radical of formula (IIq)

R₁ is H, —C(O)O—C(CH₃)₃, R₂ is —C(O)OR_(2x),—C(O)NHR_(2xx)—C(O)N(CH₃)R_(2xx) wherein R_(2x) and R_(2xx) are thegroup —(Y—ONO₂).
 10. The compounds according to claim 1 wherein informula (I) s is 1 and m is 0, s′ and s″ are 0, A is a radical offormula (IIu)

wherein a is 1 and b is 0; R₁ is H, —C(O)O—C(C₁₋₁₃)₃, R₂ is—C(O)OR_(2x), —C(O)NHR_(2xx)—C(O)N(CH₃)R_(2xx) wherein R_(2x) andR_(2xx) are the group —(Y—ONO₂), R_(K) is H.
 11. The compounds accordingto claim 1 wherein in formula (I) s and m are 1, s′ and s″ are 0, A is aradical selected from:

wherein R₁ is H or —C(O)O—C(CH₃)₃, R₂ is —C(O)OR_(2x) wherein R_(2x) isthe group —[(B)—(Y—ONO₂)] of formula (I) wherein B is

R_(a) of formula (IIa) is selected from: a) H, CH₃, isopropyl, isobutyl,sec-butyl, methylthio-(CH₂)₂—, benzyl, C₆H₅—CH₂—CH₂—,3-triptophanyl-CH₂—, NH₂—CO—CH₂—, NH₂—CO—(CH₂)₂—, 4-imidazolyl-CH₂—; b)HS—CH₂—; c) R_(x)O—CH₂—, R_(x)O—CH(CH₃)— or (R_(x)O)-p-C₆H₄—CH₂—,wherein R_(x) is H; d) R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—, wherein R_(g) isOH, (CH₃)₃C—O—, or the group R_(gg):

e) R_(h)NH(CH₂)_(p)— or R_(i)NH(═NH)NH—(CH₂)₃— wherein p is an integerequal to 3 or 4, R_(h) is H or (CH₃)₃C—OC(O)—, R_(i) is H; R_(L) offormula (IIl) is H.
 12. The compounds according to claim 1 wherein informula (I) s and s′ are 1 and m, m′ are 0, s″ is 0, A is a radical offormula (IIa)

wherein R₁ is —C(O)R_(1x), or —C(O)OR_(1x) wherein R_(1x) is one of thegroups —(Y—ONO₂) or —(Y′—ONO₂), R₂ is —C(O)OH, —C(O)—OC(CH₃)₃; or R₂ isthe group R₄

R_(a) is selected from: b) R_(bx)C(O)—S—CH₂—, R_(bx)—OC(O)—S—CH₂—,R_(bx)—NH—C(O)S—CH₂— wherein R_(bx) is one of the groups —(Y—ONO₂) or—(Y′—ONO₂); c) R_(x)O—CH₂—, R_(x)O—CH(CH₃)—, (R_(x)O)-p-C₆H₄—CH₂—,wherein R_(x) is R_(xx)C(O)—, R_(xx)C(O)— or R_(xx)NHC(O)— whereinR_(xx) is one of the groups —(Y—ONO₂) or —(Y′—ONO₂); d) R_(g)C(O)CH₂—,R_(g)C(O)(CH₂)₂—, wherein R_(g) is R_(gx)—O—, R_(gxx)—NH—, whereinR_(gx) and R_(gxx) are one of the groups —(Y—ONO₂) or —(Y′—ONO₂) offormula (I); e) R_(h)NH(CH₂)_(p)— wherein p is an integer equal to 3 or4, R_(h) is R_(hh)—C(O)— or R_(hh)—OC(O)— wherein R_(hh) is one of thegroups —(Y—ONO₂) or —(Y′—ONO₂), or R_(i)NH(═NH)NH—(CH₂)₃— wherein R_(i)is R_(ii)C(O)— or R_(ii)OC(O)— wherein R_(ii) is one of the groups—(Y—ONO₂) or —(Y′—ONO₂).
 13. The compounds according to claim 1 whereinin formula (I) s and s′ are 1 and m, m′ are 0, s″ is 0, A is a radicalof formula (IIa) or (IIl)

wherein R₁ is —C(O)R_(1x), —C(O)OR_(1x) wherein R_(1x) is one of thegroups —(Y—ONO₂) or —(Y′—ONO₂) of formula (I); R₂ is —C(O)OR_(2x),—C(O)NHR_(2xx), —C(O)N(CH)R_(2xx), wherein R_(2x) and R_(2xx) are one ofthe groups —(Y—ONO₂) or —(Y′—ONO₂) of formula (I) below defined; R_(a)is selected from: a) H, CH₃, isopropyl, isobutyl, sec-butyl,methylthio-(CH₂)₂—, benzyl, C₆H₅—CH₂—CH₂—, 3-triptophanyl-CH₂—,NH₂—CO—CH₂—, NH₂—CO—(CH₂)₂—, 4-imidazolyl-CH₂—; R_(L) in formula MD isH.
 14. The compounds according to claim 1 wherein in formula (I) s ands′ are 1, m is 1, m′ is 0, s″ is 0, A is a radical of formula

wherein R₁ is —C(O)R_(1x), —C(O)OR_(1x) wherein R_(1x) is —(Y—ONO₂); R₂is —C(O)OR_(2x), wherein R_(2x) is the group —[B—(Y′—ONO₂)] wherein B is

R_(a) is selected from: H, CH₃, isopropyl, isobutyl, sec-butyl,methylthio-(CH₂)₂—, benzyl, C₆H₅—CH₂—CH₂—, 3-triptophanyl-CH₂—,NH₂—CO—CH₂— —NH₂—CO—(CH₂)₂—, 4-imidazolyl-CH₂—; R_(L) in formula (IIl)is H.
 15. The compounds according to claim 1 wherein in formula (I) sand s′ are 1, and s″ are 0, m and m′ are 0, A is a radical of formula

wherein R₁ is —C(O)R_(1x) or —C(O)OR_(1x) wherein R_(1x) is one of thegroups —(Y—ONO₂) or (Y′—ONO₂); R₂ is —C(O)OR_(2x), —C(O)NHR_(2xx) or—C(O)N(CH₃)R_(2xx), wherein R_(2x) and R_(2xx) are one of the groups—(Y—ONO₂) or —(Y′—ONO₂); R_(a) is selected from: b) HS—CH₂—; c)R_(x)O—CH₂—, R_(x)O—CH(CH₃)—, (R_(x)O)-p-C₆H₄—CH₂—, wherein R_(x) is H,d) R_(g)C(O)CH₂— or R_(g)C(O)(CH₂)₂—, wherein R_(g) is OH, (CH₃)₃CO—, orthe group R_(gg):

e) R_(h)NH(CH₂)_(p)— or R_(i)NH(═NH)NH—(CH₂)₃—, wherein p is an integerequal to 3 or 4, R_(h) is H, (CH₃)₃C—OC(O)—, R_(i) is H;
 16. Thecompounds according to claim 1 wherein in formula (I) s and s′ are 1 andm, m′ are 0, s″ is 0, A is a radical of formula

wherein R₁ is H or —C(O)O—C(CH₃)₃, R₂ is —C(O)OR_(2x), —C(O)NHR_(2xx),—C(O)N(CH₃)R_(2xx) wherein R_(2x) and R_(2xx) are one of the groups—(Y—ONO₂) or —(Y′—ONO₂); R_(a) is selected from: b) R_(bx)C(O)—S—CH₂—,R_(bx)OC(O)—S—CH₂—, R_(bx)NH—C(O)S—CH₂— wherein R_(bx) is one of thegroups —(Y—ONO₂) or —(Y′—ONO₂); c) R_(x)O—CH₂—, R_(x)O—CH(CH₃)—,(R_(x)O)-p-C₆H₄—CH₂—, wherein R_(x) is R_(xx)C(O)—, R_(xx)OC(O)— orR_(xx)NHC(O)— wherein R_(xx) is one the groups —(Y—ONO₂) or —(Y′—ONO₂);e) R_(h)NH(CH₂)_(p)— wherein p is 3 or 4, and R_(h) is R_(hh)C(O)— orR_(hh)OC(O)— wherein R_(hh) is one the groups —(Y—ONO₂) or —(Y′—ONO₂);or R_(a) is R_(i)NH(═NH)NH—(CH₂)₃— wherein R_(i) is R_(ii)C(O)— orR_(ii)OC(O)— wherein R_(ii) is one the groups —(Y—ONO₂) or —(Y′—ONO₂).17. The compounds according to claim 1 wherein in formula (I) s and s′are 1 and m, m′ are 0, s″ is 0, A is a radical of formula

wherein R_(i) is H or —C(O)O—C(CH₃)₃, R₂ is —C(O)OR_(2x),—C(O)NHR_(2xx), —C(O)N(CH₃)R_(2xx) wherein R_(2x) and R_(2xx) are one ofthe groups —(Y—ONO₂) or —(Y′—ONO₂); R_(a) is selected from: d)R_(g)C(O)CH₂—, R_(g)C(O)(CH₂)₂—, wherein R₉ is R_(g)—NH—,R_(gxx)N(CH₃)—, wherein R_(gx) and R_(gxx) are one of the groups—(Y—ONO₂) or —(Y′—ONO₂).
 18. The compounds according to claim 1 whereinin formula (I) s, s′ and s″ are 1, in, m′ and m″ are 0, A is a radicalof formula

wherein R₁ is —C(O)R_(1x), —C(O)OR_(1x) wherein R_(1x) is one of thegroups —(Y—ONO₂) or —(Y′—ONO₂) or —(Y″—ONO₂); R₂ is —C(O)OR_(2x),—C(O)NHR_(2xx), —C(O)N(CH₃)R_(2xx) wherein R_(2x) and R_(2xx) are one ofthe groups —(Y—ONO₂) or —(Y′—ONO₂) or —(Y″—ONO₂); R_(a) is selectedfrom: b) R_(bx)C(O)—S—CH₂—, R_(bx)OC(O)—S—CH₂—, R_(bx)NH—C(O)S—CH₂—wherein R_(bx) is one of the groups —(Y—ONO₂) or —(Y′—ONO₂) or—(Y″—ONO₂); c) R_(x)O—CH₂—, R_(x)O—CH(CH₃)—, (R_(x)O)-p-C₆H₄—CH₂—,wherein R_(x) is R_(xx)C(O)—, R_(xx)OC(O)— or R_(xx)NHC(O)— whereinR_(xx) is one of the groups —(Y—ONO₂) or —(Y′—ONO₂) or —(Y″—ONO₂); d)R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—, wherein R_(g) is R_(gx)O—, R_(gxx)—NH—,R_(gxx)—N(CH₃)—, wherein R_(gx) and R_(gxx) are one of the groups—(Y—ONO₂) or —(Y′—ONO₂) or —(Y″—ONO₂), e) R_(h)NH(CH₂)_(p)— wherein p is3 or 4, and R_(h) is R_(hh)C(O)— or R_(hh)OC(O)— wherein R_(hh) is oneof the groups —(Y—ONO₂) or —(Y″—ONO₂) or —(Y″—ONO₂), or R_(a) isR_(i)NH(═NH)NH—(CH₂)₃— wherein R_(i) is R_(ii)C(O)— or R_(ii)OC(O)—wherein R_(ii) is one of the groups —(Y—ONO₂) or —(Y′—ONO₂) or—(Y″—ONO₂).
 19. The compounds according to claim 1 wherein in formula(I) s and s′ are 1, m and m′ are 0, s″is 0, A is a radical of formula

wherein R₁ is H or —C(O)—OC(CH₃)₃; R₃ is —OC(O)R_(3x), OC(O)OR_(3x),—OC(O)—NHR_(3x), wherein R_(3x) is one of the groups —(Y—ONO₂) or—(Y′—ONO₂); R_(s) is selected from: b″) R_(bx)—C(O)—S—CH₂—,R_(bx)—OC(O)—S—CH₂—, R_(bx)—NH—C(O)S—CH₂— wherein R_(bx) is one of thegroups —(Y—ONO₂) or —(Y′—ONO₂); c″) R_(x)O—CH₂—, R_(x)O—CH(CH₃)—,(R_(x)O)-p-C₆H₄—CH₂—, wherein R_(x) is R_(xx)C(O)—, R_(xx)OC(O)—,R_(xx)NHC(O)— wherein R_(xx) is one of the groups —(Y—ONO₂) or—(Y′—ONO₂); d″) R_(g)C(O)CH₂, R_(g)C(O)(CH₂)₂—, wherein R_(g) isR_(gx)O— or R_(gxx)NH— wherein R_(gx) and R_(gxx) are each independentlyone of the groups —(Y—ONO₂) or —(Y′—ONO₂); e″) R_(h)NH(CH₂)_(p)— whereinp is 3 or 4 and R_(h) is R_(hh)C(O)— or R_(hh)OC(O)— wherein R_(hh) isone of the groups —(Y—ONO₂) or —(Y′—ONO₂), or R₃ isR_(i)NH(═NH)NH—(CH₂)₃—, wherein R_(i) is R_(ii)C(O)— or R_(ii)OC(O)—wherein R_(ii) is one of the groups —(Y—ONO₂) or —(Y′—ONO₂);
 20. Acompound according to claim 4 selected from:


21. A compound according to claim 5 selected from:


22. A compound according to claim 6 selected from:


23. A compounds according to claim 7 selected from:


24. A compound according to claim 8 selected from:


25. A compound according to claim 9 selected from:


26. A compound according to claim 10 selected from:


27. A compound according to claim 11 selected from:


28. A compound according to claim 12 selected from:


29. A compound according to claim 13 selected from:


30. A compound according to claim 14 is selected from:


31. A compound according to claim 15 selected from:


32. A compound according to claim 16 selected from:


33. A compound according to claim 17 selected from:


34. A compounds according to claim 18 selected from:


35. A compound according to claim 19 selected from:


36. Compounds according to claim 1 for use as medicaments.
 37. Compoundsaccording to claim 1 for use in the treatment of cardiovasculardiseases, inflammation, pain, fever, gastrointestinal disorders,ophthalmic diseases including glaucoma, hepatic disorders, renaldiseases, respiratory disorders, immunological diseases, bone metabolismdysfunctions, central and peripheral nervous system diseases, sexualdysfunctions, infectious diseases, for the inhibition of plateletaggregation and platelet adhesion, for treating pathological conditionsresulting from abnormal cell proliferation and vascular diseases. 38.Pharmaceutical compositions comprising a compound according to claim 1and a pharmaceutical acceptable eccipient.
 39. A composition comprisingat least a compound of formula (I) according to claim 1 and at least onetherapeutic agent selected from anti-inflammatory drugs, drugs used totreat cardiovascular diseases, drugs for treating ocular diseases, drugsfor treating respiratory disorders.
 40. The composition according toclaim 39 for use as medicament.
 41. The composition according to claim39 for use in the treatment of cardiovascular diseases, inflammation,pain, fever, gastrointestinal disorders, ophthalmic diseases includingglaucoma, hepatic disorders, renal diseases, respiratory disorders,immunological diseases, bone metabolism dysfunctions, central andperipheral nervous system diseases, sexual dysfunctions, infectiousdiseases, for the inhibition of platelet aggregation and plateletadhesion, for treating pathological conditions resulting from abnormalcell proliferation and vascular diseases.
 42. The composition accordingto claim 39 wherein the two components are administered simultaneouslyor sequentially.
 43. Pharmaceutical composition comprising thecomposition according to claim 39 and a pharmaceutical acceptableeccipient.
 44. A compound selected from: 3-(nitrooxy)propyl2-(tert-butoxycarbonylamino)-4-phenyl butanoate, 3-(nitrooxy)propyl2-amino-4-phenylbutanoate, 3-(nitrooxy)propyl 2-amino-4-phenylbutanoatehydrochloride, 4-(nitrooxy)butyl2-(tert-butoxycarbonylamino)-4-phenylbutanoate, 4-(nitrooxy)butyl2-amino-4-phenylbutanoate, 4-(nitrooxy)butyl 2-amino-4-phenylbutanoatehydrochloride, (2-(nitrooxy)ethoxy)methyl2-(tert-butoxycarbonylamino)-4-phenyl butanoate,(2-(nitrooxy)ethoxy)methyl 2-amino-4-phenylbutanoate,(2-(nitrooxy)ethoxy)methyl 2-amino-4-phenylbutanoate hydrochloride,1-tert-butyl 2-(4-(nitrooxy)butyl)pyrrolidine-1,2-dicarboxylate,4-(nitrooxy)butyl pyrrolidine-2-carboxylate, 4-(nitrooxy)butylpyrrolidine-2-carboxylate hydrochloride, 1-tert-butyl2-(3-(nitrooxy)propyl)pyrrolidine-1,2-dicarboxylate, 3-(nitrooxy)propylpyrrolidine-2-carboxylate, 3-(nitrooxy)propyl pyrrolidine-2-carboxylatehydrochloride, for use as medicament.
 45. A compound selected from:3-(nitrooxy)propyl 2-(tert-butoxycarbonylamino)-4-phenyl butanoate,3-(nitrooxy)propyl 2-amino-4-phenylbutanoate, 3-(nitrooxy)propyl2-amino-4-phenylbutanoate hydrochloride, 4-(nitrooxy)butyl2-(tert-butoxycarbonylamino)-4-phenylbutanoate, 4-(nitrooxy)butyl2-amino-4-phenylbutanoate, 4-(nitrooxy)butyl 2-amino-4-phenylbutanoatehydrochloride, (2-(nitrooxy)ethoxy)methyl2-(tert-butoxycarbonylamino)-4-phenyl butanoate,(2-(nitrooxy)ethoxy)methyl 2-amino-4-phenylbutanoate,(2-(nitrooxy)ethoxy)methyl 2-amino-4-phenyl butanoate hydrochloride,1-tert-butyl 2-(4-(nitrooxy)butyl)pyrrolidine-1,2-dicarboxylate,4-(nitrooxy)butyl pyrrolidine-2-carboxylate, 4-(nitrooxy)butylpyrrolidine-2-carboxylate hydrochloride, 1-tert-butyl2-(3-(nitrooxy)propyl)pyrrolidine-1,2-dicarboxylate, 3-(nitrooxy)propylpyrrolidine-2-carboxylate, 3-(nitrooxy)propyl pyrrolidine-2-carboxylatehydrochloride for use in the treatment of cardiovascular diseases,inflammation, pain, fever, gastrointestinal disorders, ophthalmicdiseases including glaucoma, hepatic disorders, renal diseases,respiratory disorders, immunological diseases, bone metabolismdysfunctions, central and peripheral nervous system diseases, sexualdysfunctions, infectious diseases, for the inhibition of plateletaggregation and platelet adhesion, for treating pathological conditionsresulting from abnormal cell proliferation and vascular diseases.
 46. Acomposition comprising a compound selected from: 3-(nitrooxy)propyl2-(tert-butoxycarbonylamino)-4-phenyl butanoate, 3-(nitrooxy)propyl2-amino-4-phenylbutanoate, 3-(nitrooxy)propyl 2-amino-4-phenylbutanoatehydrochloride, 4-(nitrooxy)butyl2-(tert-butoxycarbonylamino)-4-phenylbutanoate, 4-(nitrooxy)butyl2-amino-4-phenylbutanoate, 4-(nitrooxy)butyl 2-amino-4-phenylbutanoatehydrochloride, (2-(nitrooxy)ethoxy)methyl2-(tert-butoxycarbonylamino)-4-phenyl butanoate,(2-(nitrooxy)ethoxy)methyl 2-amino-4-phenylbutanoate,(2-(nitrooxy)ethoxy)methyl 2-amino-4-phenyl butanoate hydrochloride,1-tert-butyl 2-(4-(nitrooxy)butyl)pyrrolidine-1,2-dicarboxylate,4-(nitrooxy)butyl pyrrolidine-2-carboxylate, 4-(nitrooxy)butylpyrrolidine-2-carboxylate hydrochloride, 1-tert-butyl2-(3-(nitrooxy)propyl)pyrrolidine-1,2-dicarboxylate, 3-(nitrooxy)propylpyrrolidine-2-carboxylate, 3-(nitrooxy)propyl pyrrolidine-2-carboxylatehydrochloride and at least one therapeutic agent selected fromanti-inflammatory drugs, drugs used to treat cardiovascular diseases,drugs for treating ocular diseases, drugs for treating respiratorydisorders.
 47. The composition according to claim 46 for use in thetreatment of cardiovascular diseases, inflammation, pain, fever,gastrointestinal disorders, ophthalmic diseases including glaucoma,hepatic disorders, renal diseases, respiratory disorders, immunologicaldiseases, bone metabolism dysfunctions, central and peripheral nervoussystem diseases, sexual dysfunctions, infectious diseases, for theinhibition of platelet aggregation and platelet adhesion, for treatingpathological conditions resulting from abnormal cell proliferation andvascular diseases.
 48. The composition according to claim 46 wherein thetwo components are administered simultaneously or sequentially. 49.Pharmaceutical composition comprising the composition according to claim46 and a pharmaceutical acceptable excipient.